Chondroprotective functions of neutrophil-derived extracellular vesicles by promoting the production of secreted frizzled-related protein 5 in cartilage.
Keita Kitahara, Taku Ebata, Chen Liyile, Yoshio Nishida, Yuki Ogawa, Taiki Tokuhiro, Junki Shiota, Tatsuya Nagano, Taichi E Takasuka, Tsutomu Endo, Tomohiro Shimizu, Hend Alhasan, Tsuyoshi Asano, Daisuke Takahashi, Kentaro Homan, Tomohiro Onodera, Ken Kadoya, M Alaa Terkawi, Norimasa Iwasaki
Cell communication and signaling : CCS, 22, 1, 569, 569, 2024年11月27日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Osteoarthritis (OA) is the most common degenerative joint disease characterized by cartilage degradation and various degrees of inflammation in the synovium. Growing evidence highlights that neutrophil extracellular vesicles (EVs) play a protective role in arthritic joints by promoting the resolution of inflammation and the synthesis of proteoglycans in cartilage. However, this homeostatic function is dependent on the activation state of neutrophils and the surrounding environment/tissues. Hence, we explored the chondroprotective functions of neutrophil-derived EVs under different stimulation conditions and the underlying molecular mechanism. METHODS: Human blood-derived neutrophils, murine bone marrow-derived neutrophils, C-28I2 cells and primary chondrocytes were used. Neutrophils were stimulated with different cytokines, and their EVs were isolated for chondrocyte stimulation and further subjected to RNA-sequencing analysis. Two experimental murine OA models were used, and the treatment was performed by intraarticular injections. RESULTS: Conditioned medium from neutrophils stimulated with TGF-β (N-β) had the greatest inhibitory effect on the expression of catabolic factors in stimulated chondrocytes. These protective effects were not impaired when conditioned medium of N-β from AnxA1-deficient mice was used. Consistent with these results, EVs isolated from N-β significantly reduced the expression of catabolic factors in stimulated chondrocytes. Bulk RNA-seq analysis revealed that secreted frizzled-related protein 5 (SFRP5) is upregulated in N-β-EV-stimulated chondrocytes. Furthermore, recombinant SFRP5 treatment significantly reduced the expression of catabolic factors in vitro and catabolic process in experimental murine OA models. CONCLUSIONS: The current study emphasizes the potential therapeutic application of neutrophils in OA and provides new knowledge on the molecular mechanisms underlying their function.

Dynamic transcriptome analysis of osteal macrophages identifies distinct subset with senescence features in experimental osteoporosis.
Yoshio Nishida, M Alaa Terkawi, Gen Matsumae, Shunichi Yokota, Taiki Tokuhiro, Yuki Ogawa, Hotaka Ishizu, Junki Shiota, Tsutomu Endo, Hend Alhasan, Taku Ebata, Keita Kitahara, Tomohiro Shimizu, Daisuke Takahashi, Masahiko Takahata, Ken Kadoya, Norimasa Iwasaki
JCI insight, 2024年10月31日, ［国際誌］
英語, 研究論文（学術雑誌）, Given the potential fundamental function of osteal macrophages in bone pathophysiology, we study here their precise function in experimental osteoporosis. Gene profiling of osteal macrophages from ovariectomized mice demonstrated the upregulation of genes that were involved in oxidative stress, cell senescence and apoptotic process. A scRNA-seq analysis revealed that osteal macrophages were heterogenously clustered into 6 subsets that expressed proliferative, inflammatory, anti-inflammatory and efferocytosis gene signatures. Importantly, postmenopausal mice exhibited a 20-fold increase in subset-3 that showed a typical gene signature of cell senescence and inflammation. These findings suggest that the decreased production of estrogen due to postmenopause altered the osteal macrophages subsets, resulting in a shift toward cell senescence and inflammatory conditions in the bone microenvironment. Furthermore, adoptive macrophage transfer onto calvarial bone was performed and mice that received oxidative-stressed macrophages exhibited greater osteolytic lesions than control macrophages, suggesting the role of these cells in development of inflammaging in bone microenvironment. Consistently, depletion of senescent cells and oxidative-stressed macrophages subset alleviated the excessive bone loss in postmenopausal mice. Our data provided a new insight into the pathogenesis of osteoporosis and sheds light on a new therapeutic approach for the treatment/prevention of postmenopausal osteoporosis.

Ossification of the posterior longitudinal ligament is linked to heterotopic ossification of the ankle/foot tendons.
Tsutomu Endo, Masahiko Takahata, Yoshinao Koike, Ryo Fujita, Daisuke Yoneoka, Masahiro Kanayama, Ken Kadoya, Tomoka Hasegawa, Mohamad Alaa Terkawi, Katsuhisa Yamada, Hideki Sudo, Taku Ebata, Misaki Ishii, Norimasa Iwasaki
Journal of bone and mineral metabolism, 2024年06月08日, ［国内誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Systemic osteogenesis has been speculated to be involved in the pathogenesis of ossification of the posterior longitudinal ligament (OPLL). Our purpose was to compare the radiologic prevalence and severity of heterotopic ossification in foot tendons of Japanese patients with OPLL and to determine their association with systemic heterotopic ossification. MATERIALS AND METHODS: Clinical and radiographic data of 114 patients with OPLL were collected from 2020 to 2022. Control data were extracted from a medical database of 362 patients with ankle radiographs. Achilles and plantar tendon ossification were classified as grades 0-4, and the presence of osteophytes at five sites in the foot/ankle joint was assessed by radiography. Factors associated with the presence and severity of each ossification were evaluated by multivariable logistic regression and linear regression analysis. RESULTS: The prevalence of Achilles and plantar tendon ossification (grade ≥ 2) was 4.0-5.5 times higher in patients with OPLL (40-56%) than in the controls (10-11%). The presence of Achilles tendon ossification was associated with OPLL, age, and coexisting plantar tendon ossification, and was most strongly associated with OPLL (standardized regression coefficient, 0.79; 95% confidence interval, 1.34-2.38). The severity of Achilles and plantar tendon ossification was associated with the severity of ossification of the entire spinal ligament. CONCLUSIONS: The strong association of foot tendon ossification with OPLL suggests that patients with OPLL have a systemic osteogenesis background. These findings will provide a basis for exploring new treatment strategies for OPLL, including control of metabolic abnormalities.

炎症収束型好中球由来細胞外小胞による軟骨細胞抗異化作用についての検討
北原 圭太, 江畑 拓, 照川 アラー, 清水 智弘, 遠藤 努, 浅野 毅, 高橋 大介, 角家 健, 岩崎 倫政
日本整形外科学会雑誌, 97, 8, S1667, S1667, (公社)日本整形外科学会, 2023年08月
日本語

ラット坐骨神経を使用した慢性絞扼性神経障害の新規モデル開発
山本 康弘, 角家 健, 内藤 聖人, 石島 旨章, 岩崎 倫政
日本整形外科学会雑誌, 97, 8, S1757, S1757, (公社)日本整形外科学会, 2023年08月
日本語

炎症収束型好中球由来細胞外小胞による軟骨細胞抗異化作用についての検討
北原 圭太, 江畑 拓, 照川 アラー, 清水 智弘, 遠藤 努, 浅野 毅, 高橋 大介, 角家 健, 岩崎 倫政
日本整形外科学会雑誌, 97, 8, S1667, S1667, (公社)日本整形外科学会, 2023年08月
日本語

High whole-body bone mineral density in ossification of the posterior longitudinal ligament.
Ryo Fujita, Tsutomu Endo, Masahiko Takahata, Yoshinao Koike, Daisuke Yoneoka, Ryota Suzuki, Masaru Tanaka, Katsuhisa Yamada, Hideki Sudo, Tomoka Hasegawa, Mohamad Alaa Terkawi, Ken Kadoya, Norimasa Iwasaki
The spine journal : official journal of the North American Spine Society, 23, 10, 1461, 1470, 2023年07月10日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND CONTEXT: Recent studies suggest that ossification of the posterior longitudinal ligament (OPLL) is exacerbated by systemic metabolic disturbances, including obesity. However, although an increase in bone mineral density (BMD) measured at the lumbar spine has been reported in patients with OPLL, no studies have investigated the systemic BMD of patients with OPLL in detail. PURPOSE: We investigated whether patients with OPLL develop increased whole-body BMD. STUDY DESIGN: Single institution cross-sectional study. PATIENT SAMPLE: Data were collected from Japanese patients with symptomatic OPLL (OPLL [+]; n=99). Control data (OPLL [-]; n=226) without spinal ligament ossification were collected from patients who underwent spinal decompression, spinal fusion, or hip replacement surgery. OUTCOME MEASURES: Demographic data, including age, body mass index (BMI), comorbidities, history of treatment for osteoporosis, and history of vertebral and nonvertebral fractures, was obtained from all participants. In addition, whole-body BMD, including the lumbar spine, thoracic spine, femoral neck, skull, ribs, entire upper extremity, entire lower extremity, and pelvis, were measured in all participants using whole-body dual-energy X-ray absorptiometry. METHODS: Patient data were collected from 2018 to 2022. All participants were categorized based on sex, age (middle-aged [<70 years] and older adults [≥70 years]), and OPLL type (localized OPLL [OPLL only in the cervical spine], diffuse OPLL [OPLL in regions including the thoracic spine]), and OPLL [-]) and each parameter was compared. The factors associated with whole-body BMD were evaluated via multivariable linear regression analysis. RESULTS: Compared with the OPLL (-) group, the OPLL (+) group of older women had significantly higher BMD in all body parts (p<.01), and the OPLL (+) group of older men had significantly higher BMD in all body parts except the ribs, forearm, and skull (p<.01). The factors associated with increased BMD of both the femoral neck (load-bearing bone) and skull (nonload-bearing bone) were age, BMI, and coexisting diffuse OPLL in women and BMI and coexisting localized OPLL in men. CONCLUSIONS: Patients with OPLL have increased whole-body BMD regardless of sex, indicating that it is not simply due to load-bearing from obesity. These findings suggested that OPLL is associated with a systemic pathology.

Dyslipidemia as a novel risk for the development of symptomatic ossification of the posterior longitudinal ligament.
Shotaro Fukada, Tsutomu Endo, Masahiko Takahata, Masahiro Kanayama, Yoshinao Koike, Ryo Fujita, Ryota Suzuki, Toshifumi Murakami, Tomoka Hasegawa, Mohamad Alaa Terkawi, Tomoyuki Hashimoto, Kastuhisa Yamada, Hideki Sudo, Ken Kadoya, Norimasa Iwasaki
The spine journal : official journal of the North American Spine Society, 23, 9, 1287, 1295, 2023年05月07日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND CONTEXT: Obesity and visceral fat have been implicated as potential factors in the pathogenesis of the ossification of the posterior longitudinal ligament (OPLL); the details of the factors involved in OPLL remain unclear. PURPOSE: We aimed to determine the association between dyslipidemia and symptomatic OPLL. STUDY DESIGN: Single institution cross-sectional study. PATIENT SAMPLE: Data were collected from Japanese patients with OPLL (n=92) who underwent whole-spine computed tomography scanning. Control data (n=246) without any spinal ligament ossification were collected from 627 Japanese participants who underwent physical examination. OUTCOME MEASURES: Baseline information and lipid parameters, including triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from fasting blood samples were collected to assess the comorbidity of dyslipidemia. METHODS: Patient data were collected from 2020 to 2022. Patients with dyslipidemia were defined as those who were taking medication for dyslipidemia and who met one of the following criteria: TG ≥150 mg/dL, LDL-C ≥140 mg/dL, and/or HDL-C <40 mg/dL. The factors associated with OPLL development were evaluated using multivariate logistic regression analysis. RESULTS: The comorbidity of dyslipidemia in the OPLL group was more than twice that in the control group (71.7% and 35.4%, respectively). The mean body mass index (BMI) of the OPLL group was significantly higher than that of the control group (27.2 kg/m2 and 23.0 kg/m2). Multivariate logistic regression analysis revealed that dyslipidemia was associated with the development of OPLL (regression coefficient, 0.80; 95% confidence interval, 0.11-1.50). Additional risk factors included age, BMI, and diabetes mellitus. CONCLUSIONS: We demonstrated a novel association between dyslipidemia and symptomatic OPLL development using serum data. This suggests that visceral fat obesity or abnormal lipid metabolism are associated with the mechanisms of onset and exacerbation of OPLL as well as focal mechanical irritation due to being overweight.

Peripheral nerve-derived fibroblasts promote neurite outgrowth in adult dorsal root ganglion neurons more effectively than skin-derived fibroblasts.
Masato Hara, Ken Kadoya, Takeshi Endo, Norimasa Iwasaki
Experimental physiology, 108, 4, 621, 635, 2023年04月, ［国際誌］
英語, 研究論文（学術雑誌）, NEW FINDINGS: What is the central question of this study? Although fibroblasts are involved in the regenerative process associated with peripheral nerve injury, detailed information regarding their characteristics is largely lacking. What is the main finding and its importance? Nerve-derived fibroblasts have a greater neurite-promoting effect than skin-derived fibroblasts, and epineurium-derived fibroblasts can promote neurite outgrowth more effectively than parenchyma-derived fibroblasts. The epineurium-derived fibroblasts and parenchyma-derived fibroblasts have distinctly different molecular profiles, including genes of soluble factors to promote axonal growth. Fibroblasts are molecularly and functionally different depending on their localization in nerve tissue, and epineurium-derived fibroblasts might be involved in axon regeneration after peripheral nerve injury more than previously thought. ABSTRACT: Although fibroblasts (Fb) are components of a peripheral nerve involved in the regenerative process associated with peripheral nerve injury, detailed information regarding their characteristics is largely lacking. The objective of the present study was to investigate the capacity of Fb derived from peripheral nerves to stimulate the outgrowth of neurites from adult dorsal root ganglion neurons and to clarify their molecular characteristics. Fibroblasts were prepared from the epineurium and parenchyma of rat sciatic nerves and skin. The Fb derived from epineurium showed the greatest effect on neurite outgrowth, followed by the Fb derived from parenchyma, indicating that Fb derived from nerves promote neurite outgrowth more effectively than skin-derived Fb. Although both soluble and cell-surface factors contributed evenly to the neurite-promoting effect of nerve-derived Fb, in crush and transection injury models, Fb were not closely associated with regenerating axons, indicating that only soluble factors from Fb are available to regenerating axons. A transcriptome analysis revealed that the molecular profiles of these Fb were distinctly different and that the gene expression profiles of soluble factors that promote axonal growth are unique to each Fb. These findings indicate that Fb are molecularly and functionally different depending on their localization in nerve tissue and that Fb derived from epineurium might be involved more than was previously thought in axon regeneration after peripheral nerve injury.

Macrophage‐derived extracellular vesicles trigger non‐canonical pyroptosis in chondrocytes leading to cartilage catabolism in osteoarthritis
Taku Ebata, Mohamad Alaa Terkawi, Keita Kitahara, Syunichi Yokota, Junki Shiota, Yoshio Nishida, Gen Matsumae, Hend Alhasan, Masanari Hamasaki, Kazutoshi Hontani, Tomohiro Shimizu, Daisuke Takahashi, Tsutomu Endo, Tomohiro Onodera, Ken Kadoya, Norimasa Iwasaki
Arthritis & Rheumatology, 2023年03月16日, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: The severity of osteoarthritis and cartilage degeneration are highly correlated with the development of synovitis, which is mediated by the activity of inflammatory macrophages. A better understanding of intercellular communication between inflammatory macrophages and chondrocytes should aid in the discovery of novel therapeutic targets. Here, we explored the pathological role of inflammatory macrophage extracellular vesicles in cartilage degeneration. METHODS: Macrophages were stimulated by treatment with bacterial lipopolysaccharides to mimic the state of inflammatory macrophages and the resulting extracellular vesicles were harvested for chondrocyte stimulation in vitro and intraarticular injection in a mouse model. The stimulated chondrocytes were further subjected to RNA-seq analysis and other functional assays. The action of caspase-11 was disrupted in vitro using a specific siRNA or wedelolactone, and in experimental OA-murine models by the intraarticular injection of wedelolactone. RESULTS: Stimulated chondrocytes exhibited a significant elevation in the expression of chondrocyte catabolic factors. Consistent with these results, RNA-seq analyses of stimulated chondrocytes indicated that upregulated genes are mainly categorized into apoptotic process and TNF-signaling pathway which suggests the induction of apoptotic process. Moreover, these chondrocytes exhibited a significant elevation in the expression of pyroptosis-related molecules that were correlated with the expression of chondrocyte catabolic factors. The disruption of caspase-11 significantly alleviated pyroptotic and catabolic processes in stimulated chondrocytes and the pathological changes in collagenase-and joint instability-induced OA models. CONCLUSIONS: Our results provide a new insight into the pathological mechanisms of OA and suggest that non-canonical pyroptosis in chondrocytes represents an attractive therapeutic target for future treatment.

人工関節置換術後無菌性緩みの局所骨溶解におけるチミジンホスホリラーゼの機能解析
松前 元, 清水 智弘, 田 園, 高橋 大介, 江畑 拓, 照川 ヘンド, 横田 隼一, 角家 健, 照川 アラー, 岩崎 倫政
北海道整形災害外科学会雑誌, 64, 2, 59, 72, 北海道整形災害外科学会, 2023年03月
日本語, マクロファージは,炎症と病的骨吸収を惹起することで人工関節後の無菌性緩みに関与する.本研究の目的は,無菌性緩み発症におけるマクロファージ由来因子の同定とその機能解析である.まず,ポリエチレン摩耗粉とマクロファージを共培養し,RNAシークエンス解析を行った.この結果,破骨細胞分化に関与する12個の因子を同定した.この中で,チミジンホスホリラーゼ(TYMP)が最も破骨細胞を誘導した.無菌性緩み症例の血清と滑膜からTYMPが同定できた.動物実験では,TYMPは炎症細胞,破骨細胞の誘導に加え,骨吸収域を増加させた.TYMPの破骨細胞誘導機序を検証するためRNAシークエンス解析を行ったところ,Srcチロシンキナーゼの一種であるFYNが有意に上昇した.そこでFYNの抑制剤であるサラカチニブをモデルマウスに投与したところ,摩耗粉による骨吸収域が有意に低下した.以上の結果から,TYMPは人工関節無菌性緩みにおける有用な治療ターゲットとなり得ることが示唆された.(著者抄録)

末梢神経再生治療の最前線-基礎から臨床へ- シュワン細胞の軸索再生メカニズムから考える末梢神経再生治療戦略
遠藤 健, 角家 健, 鈴木 智亮, 鈴木 裕貴, 照川 アラー, 河村 太介, 岩崎 倫政
日本整形外科学会雑誌, 97, 2, S154, S154, (公社)日本整形外科学会, 2023年03月
日本語

慢性絞扼性神経障害の新規動物モデル開発と病態解明
山本 康弘, 角家 健, 内藤 聖人, 石島 旨章, 岩崎 倫政
日本整形外科学会雑誌, 97, 2, S316, S316, (公社)日本整形外科学会, 2023年03月
日本語

人工関節置換術後無菌性緩みの局所骨溶解におけるチミジンホスホリラーゼの機能解析
松前 元, 清水 智弘, 田 園, 高橋 大介, 江畑 拓, 照川 ヘンド, 横田 隼一, 角家 健, 照川 アラー, 岩崎 倫政
北海道整形災害外科学会雑誌, 64, 2, 59, 72, 北海道整形災害外科学会, 2023年03月
日本語, マクロファージは,炎症と病的骨吸収を惹起することで人工関節後の無菌性緩みに関与する.本研究の目的は,無菌性緩み発症におけるマクロファージ由来因子の同定とその機能解析である.まず,ポリエチレン摩耗粉とマクロファージを共培養し,RNAシークエンス解析を行った.この結果,破骨細胞分化に関与する12個の因子を同定した.この中で,チミジンホスホリラーゼ(TYMP)が最も破骨細胞を誘導した.無菌性緩み症例の血清と滑膜からTYMPが同定できた.動物実験では,TYMPは炎症細胞,破骨細胞の誘導に加え,骨吸収域を増加させた.TYMPの破骨細胞誘導機序を検証するためRNAシークエンス解析を行ったところ,Srcチロシンキナーゼの一種であるFYNが有意に上昇した.そこでFYNの抑制剤であるサラカチニブをモデルマウスに投与したところ,摩耗粉による骨吸収域が有意に低下した.以上の結果から,TYMPは人工関節無菌性緩みにおける有用な治療ターゲットとなり得ることが示唆された.(著者抄録)

Lumbar ossification of the ligamentum flavum reflects a strong ossification tendency of the entire spinal ligament.
Kazuha Nakabachi, Tsutomu Endo, Masahiko Takahata, Ryo Fujita, Yoshinao Koike, Ryota Suzuki, Yuichi Hasegawa, Toshifumi Murakami, Katsuhisa Yamada, Hideki Sudo, Mohamad Alaa Terkawi, Ken Kadoya, Norimasa Iwasaki
Scientific reports, 13, 1, 638, 638, 2023年01月12日, ［国際誌］
英語, 研究論文（学術雑誌）, Patients with ossification of the ligamentum flavum (OLF) in the lumbar spine may be at high risk of developing concomitant ossification of the entire spinal ligament, but the etiology remains unclear. We investigated the propensity for spinal ligament ossification in asymptomatic subjects with lumbar OLF using the data of 595 Japanese individuals receiving medical check-ups, including computed tomography (CT) scanning. The severity of OLF (total number of intervertebral segments with OLF) of the entire spine on CT was quantified using an OLF index. Subjects with OLF were grouped according to this index: localized OLF (n = 138), intermediate OLF (n = 70), and extensive OLF (n = 31). The proportion of subjects with lumbar OLF increased with increasing OLF index (localized 13.7%, intermediate 41.4%, and extensive 70.9%). Multiple regression analysis found that lumbar OLF index was associated with thoracic OLF index, and co-existence of ossification of the posterior longitudinal ligament (OPLL) of the thoracic and lumbar spine. This study showed that subjects with more multilevel lumbar OLF were more likely to develop multilevel thoracic OLF and to have coexisting OPLL. Patients with lumbar OLF may be a distinctive subgroup with a strong tendency to ossification of the entire spinal ligament.

炎症収束型好中球由来細胞外小胞による軟骨細胞における抗異化作用の検討
北原 圭太, 江畑 拓, 横田 隼一, 塩田 惇喜, 西田 善郎, 徳廣 泰貴, 清水 智弘, 浅野 毅, 高橋 大介, 角家 健, 岩崎 倫政
北海道整形災害外科学会雑誌, 65, 142nd suppl, 66, 66, 北海道整形災害外科学会, 2023年
日本語

Spinal Canal and Spinal Cord in Rat Continue to Grow Even after Sexual Maturation: Anatomical Study and Molecular Proposition.
Akihito Sotome, Ken Kadoya, Yuki Suzuki, Norimasa Iwasaki
International journal of molecular sciences, 23, 24, 2022年12月16日, ［国際誌］
英語, 研究論文（学術雑誌）, Although rodents have been widely used for experimental models of spinal cord diseases, the details of the growth curves of their spinal canal and spinal cord, as well as the molecular mechanism of the growth of adult rat spinal cords remain unavailable. They are particularly important when conducting the experiments of cervical spondylotic myelopathy (CSM), since the disease condition depends on the size of the spinal canal and the spinal cord. Thus, the purposes of the present study were to obtain accurate growth curves for the spinal canal and spinal cord in rats; to define the appropriate age in weeks for their use as a CSM model; and to propose a molecular mechanism of the growth of the adult spinal cord in rats. CT myelography was performed on Lewis rats from 4 weeks to 40 weeks of age. The vertical growth of the spinal canal at C5 reached a plateau after 20 and 12 weeks, and at T8 after 20 and 16 weeks, in males and females, respectively. The vertical growth of the C5 and T8 spinal cord reached a plateau after 24 weeks in both sexes. The vertical space available for the cord (SAC) of C5 and T8 did not significantly change after 8 weeks in either sex. Western blot analyses showed that VEGFA, FGF2, and BDNF were highly expressed in the cervical spinal cords of 4-week-old rats, and that the expression of these growth factors declined as rats grew. These findings indicate that the spinal canal and the spinal cord in rats continue to grow even after sexual maturation and that rats need to be at least 8 weeks of age for use in experimental models of CSM. The present study, in conjunction with recent evidence, proposes the hypothetical model that the growth of rat spinal cord after the postnatal period is mediated at least in part by differentiation of neural progenitor cells and that their differentiation potency is maintained by VEGFA, FGF2, and BDNF.

Molecular and Regenerative Characterization of Repair and Non-repair Schwann Cells.
Tomoaki Suzuki, Ken Kadoya, Takeshi Endo, Norimasa Iwasaki
Cellular and molecular neurobiology, 2022年10月12日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Although evidence has accumulated to indicate that Schwann cells (SCs) differentiate into repair SCs (RSCs) upon injury and that the unique phenotype of these cells allow them to provide support for peripheral nerve regeneration, the details of the RSCs are not fully understood. The findings of the current study indicate that the RSCs have enhanced adherent properties and a greater capability to promote neurite outgrowth and axon regeneration after peripheral nerve injury, compared to the non-RSCs. Further, transcriptome analyses have demonstrated that the molecular signature of the RSCs is distinctly different from that of the non-RSCs. The RSCs upregulate a group of genes that are related to inflammation, repair, and regeneration, whereas non-RSCs upregulate genes related to myelin maintenance, Notch, and aging. These findings indicate that the RSCs have markedly different cellular, regenerative, and molecular characteristics compared to the non-RSCs, even though the RSCs were just derived from non-RSCs upon injury, thus providing the basis for understanding the mechanisms related to SC mediated repair after peripheral nerve injury.

Neutrophils delay repair process in Wallerian degeneration by releasing NETs outside the parenchyma.
Yasuhiro Yamamoto, Ken Kadoya, Mohamad Alaa Terkawi, Takeshi Endo, Kohtarou Konno, Masahiko Watanabe, Satoshi Ichihara, Akira Hara, Kazuo Kaneko, Norimasa Iwasaki, Muneaki Ishijima
Life science alliance, 5, 10, 2022年10月, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Although inflammation is indispensable for the repair process in Wallerian degeneration (WD), the role of neutrophils in the WD repair process remains unclear. After peripheral nerve injury, neutrophils accumulate at the epineurium but not the parenchyma in the WD region because of the blood-nerve barrier. An increase or decrease in the number of neutrophils delayed or promoted macrophage infiltration from the epineurium into the parenchyma and the repair process in WD. Abundant neutrophil extracellular traps (NETs) were formed around neutrophils, and its inhibition dramatically increased macrophage infiltration into the parenchyma. Furthermore, inhibition of either MIF or its receptor, CXCR4, in neutrophils decreased NET formation, resulting in enhanced macrophage infiltration into the parenchyma. Moreover, inhibiting MIF for just 2 h after peripheral nerve injury promoted the repair process. These findings indicate that neutrophils delay the repair process in WD from outside the parenchyma by inhibiting macrophage infiltration via NET formation and that neutrophils, NETs, MIF, and CXCR4 are therapeutic targets for peripheral nerve regeneration.

High-Throughput Screening Assay Identifies Berberine and Mubritinib as Neuroprotection Drugs for Spinal Cord Injury via Blood-Spinal Cord Barrier Protection.
Yuki Suzuki, Shinsuke Nakagawa, Takeshi Endo, Akihito Sotome, Rufei Yuan, Tsuyoshi Asano, Satoko Otsuguro, Katsumi Maenaka, Norimasa Iwasaki, Ken Kadoya
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 19, 6, 1976, 1991, 2022年09月30日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Because the breakdown of the blood-brain spinal cord barrier (BBSCB) worsens many central nervous system (CNS) diseases, prevention of BBSCB breakdown has been a major therapeutic target, especially for spinal cord injury (SCI). However, effective drugs that protect BBSCB function have yet to be developed. The purpose of the current study was 1) to develop a high-throughput screening assay (HTSA) to identify candidate drugs to protect BBSCB function, 2) to identify candidate drugs from existing drugs with newly developed HTSA, and 3) to examine the therapeutic effects of candidate drugs on SCI. Our HTSA included a culture of immortalized human brain endothelial cells primed with candidate drugs, stress with H2O2, and evaluation of their viability. A combination of the resazurin-based assay with 0.45 mM H2O2 qualified as a reliable HTSA. Screening of 1,570 existing drugs identified 90 drugs as hit drugs. Through a combination of reproducibility tests, exclusion of drugs inappropriate for clinical translation, and dose dependency tests, berberine, mubritinib, and pioglitazone were identified as a candidate. An in vitro BBSCB functional test revealed that berberine and mubritinib, but not pioglitazone, protected BBSCB from oxygen-glucose deprivation and reoxygenation stress. Additionally, these two drugs minimized BBSCB breakdown 1 day after cervical SCI in mice. Furthermore, berberine and mubritinib reduced neuronal loss and improved gait performance 8 weeks after SCI. Collectively, the current study established a useful HTSA to identify potential neuroprotective drugs by maintaining BBSCB function and demonstrated the neuroprotective effect of berberine and mubritinib after SCI.

骨粗鬆症における骨マクロファージのサブタイプ変化とその機能解析
松前 元, 照川 アラー, 横田 隼一, 江畑 拓, 高橋 大介, 角家 健, 岩崎 倫政
日本整形外科学会雑誌, 96, 8, S1536, S1536, (公社)日本整形外科学会, 2022年09月
日本語

ウェアラブルデバイスの有用性 足部ウェアラブルデバイスによる歩行解析の妥当性と臨床研究の実際
角家 健, 宝満 健太郎, 岩崎 倫政
日本関節病学会誌, 41, 3, 209, 209, (一社)日本関節病学会, 2022年09月
日本語

炎症収束型好中球由来細胞外小胞による軟骨細胞抗異化作用の検討
北原 圭太, 江畑 拓, 清水 智弘, 浅野 毅, 照川 アラー, 高橋 大介, 角家 健, 岩崎 倫政
日本整形外科学会雑誌, 96, 8, S1559, S1559, (公社)日本整形外科学会, 2022年09月
日本語

軟骨細胞パイロトーシス制御による軟骨変性抑制効果
江畑 拓, 照川 アラー, 横田 隼一, 照川 ヘンド, 松前 元, 清水 智弘, 高橋 大介, 小野寺 智洋, 角家 健, 岩崎 倫政
日本整形外科学会雑誌, 96, 8, S1580, S1580, (公社)日本整形外科学会, 2022年09月
日本語

Inhibitory role of Annexin A1 in pathological bone resorption and therapeutic implications in periprosthetic osteolysis.
Hend Alhasan, Mohamad Alaa Terkawi, Gen Matsumae, Taku Ebata, Yuan Tian, Tomohiro Shimizu, Yoshio Nishida, Shunichi Yokota, Fayna Garcia-Martin, Mahmoud M Abd Elwakil, Daisuke Takahashi, Mahmoud A Younis, Hideyoshi Harashima, Ken Kadoya, Norimasa Iwasaki
Nature communications, 13, 1, 3919, 3919, 2022年07月07日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, There is currently no therapy available for periprosthetic osteolysis, the most common cause of arthroplasty failure. Here, the role of AnxA1 in periprosthetic osteolysis and potential therapeutics were investigated. Reducing the expression of AnxA1 in calvarial tissue was found to be associated with increased osteolytic lesions and the osteolytic lesions induced by debris implantation were more severe in AnxA1-defecient mice than in wild-type mice. AnxA1 inhibits the differentiation of osteoclasts through suppressing NFκB signaling and promoting the PPAR-γ pathway. Administration of N-terminal-AnxA1 (Ac2-26 peptide) onto calvariae significantly reduced osteolytic lesions triggered by wear debris. These therapeutic effects were abrogated in mice that had received the PPAR-γ antagonist, suggesting that the AnxA1/PPAR-γ axis has an inhibitory role in osteolysis. The administration of Ac2-26 suppressed osteolysis induced by TNF-α and RANKL injections in mice. These findings indicate that AnxA1 is a potential therapeutic agent for the treatment of periprosthetic osteolysis.

Retrograde Axonal Transport of Liposomes from Peripheral Tissue to Spinal Cord and DRGs by Optimized Phospholipid and CTB Modification.
Takafumi Fukui, Hironao Tateno, Takashi Nakamura, Yuma Yamada, Yusuke Sato, Norimasa Iwasaki, Hideyoshi Harashima, Ken Kadoya
International journal of molecular sciences, 23, 12, 2022年06月15日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Despite recent advancements in therapeutic options for disorders of the central nervous system (CNS), the lack of an efficient drug-delivery system (DDS) hampers their clinical application. We hypothesized that liposomes could be optimized for retrograde transport in axons as a DDS from peripheral tissues to the spinal cord and dorsal root ganglia (DRGs). Three types of liposomes consisting of DSPC, DSPC/POPC, or POPC in combination with cholesterol (Chol) and polyethylene glycol (PEG) lipid were administered to sciatic nerves or the tibialis anterior muscle of mature rats. Liposomes in cell bodies were detected with infrared fluorescence of DiD conjugated to liposomes. Three days later, all nerve-administered liposomes were retrogradely transported to the spinal cord and DRGs, whereas only muscle-administered liposomes consisting of DSPC reached the spinal cord and DRGs. Modification with Cholera toxin B subunit improved the transport efficiency of liposomes to the spinal cord and DRGs from 4.5% to 17.3% and from 3.9% to 14.3% via nerve administration, and from 2.6% to 4.8% and from 2.3% to 4.1% via muscle administration, respectively. Modification with octa-arginine (R8) improved the transport efficiency via nerve administration but abolished the transport capability via muscle administration. These findings provide the initial data for the development of a novel DDS targeting the spinal cord and DRGs via peripheral administration.

IL4 stimulated macrophages promote axon regeneration after peripheral nerve injury by secreting uPA to stimulate uPAR upregulated in injured axons.
Yuki Matsui, Ken Kadoya, Yusuke Nagano, Takeshi Endo, Masato Hara, Gen Matsumae, Tomoaki Suzuki, Yasuhiro Yamamoto, Mohamad Alaa Terkawi, Norimasa Iwasaki
Cellular and molecular life sciences : CMLS, 79, 6, 289, 289, 2022年05月10日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Accumulating evidences suggest that M2 macrophages are involved with repair processes in the nervous system. However, whether M2 macrophages can promote axon regeneration by directly stimulating axons nor its precise molecular mechanism remains elusive. Here, the current study demonstrated that typical M2 macrophages, which were generated by IL4 simulation, had the capacity to stimulate axonal growth by their direct effect on axons and that the graft of IL4 stimulated macrophages into the region of Wallerian degeneration enhanced axon regeneration and improved functional recovery after PNI. Importantly, uPA (urokinase plasminogen activator)-uPA receptor (uPAR) was identified as the central axis underlying the axon regeneration effect of IL4 stimulated macrophages. IL4 stimulated macrophages secreted uPA, and its inhibition abolished their axon regeneration effect. Injured but not intact axons expressed uPAR to be sensitive to uPA. These results unveil a cellular and molecular mechanism underlying the macrophage related axon regeneration and provide a basis of a novel therapy for PNI.

Low-Grade Inflammation in the Pathogenesis of Osteoarthritis: Cellular and Molecular Mechanisms and Strategies for Future Therapeutic Intervention.
M Alaa Terkawi, Taku Ebata, Shunichi Yokota, Daisuke Takahashi, Tsutomu Endo, Gen Matsumae, Tomohiro Shimizu, Ken Kadoya, Norimasa Iwasaki
Biomedicines, 10, 5, 2022年05月10日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Osteoarthritis (OA) is a musculoskeletal disease characterized by cartilage degeneration and stiffness, with chronic pain in the affected joint. It has been proposed that OA progression is associated with the development of low-grade inflammation (LGI) in the joint. In support of this principle, LGI is now recognized as the major contributor to the pathogenesis of obesity, aging, and metabolic syndromes, which have been documented as among the most significant risk factors for developing OA. These discoveries have led to a new definition of the disease, and OA has recently been recognized as a low-grade inflammatory disease of the joint. Damage-associated molecular patterns (DAMPs)/alarmin molecules, the major cellular components that facilitate the interplay between cells in the cartilage and synovium, activate various molecular pathways involved in the initiation and maintenance of LGI in the joint, which, in turn, drives OA progression. A better understanding of the pathological mechanisms initiated by LGI in the joint represents a decisive step toward discovering therapeutic strategies for the treatment of OA. Recent findings and discoveries regarding the involvement of LGI mediated by DAMPs in OA pathogenesis are discussed. Modulating communication between cells in the joint to decrease inflammation represents an attractive approach for the treatment of OA.

Comprehensive validation of a wearable foot sensor system for estimating spatiotemporal gait parameters by simultaneous three-dimensional optical motion analysis.
Kentaro Homan, Keizo Yamamoto, Ken Kadoya, Naoki Ishida, Norimasa Iwasaki
BMC sports science, medicine & rehabilitation, 14, 1, 71, 71, 2022年04月17日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Use of a wearable gait analysis system (WGAS) is becoming common when conducting gait analysis studies due to its versatility. At the same time, its versatility raises a concern about its accuracy, because its calculations rely on assumptions embedded in its algorithms. The purpose of the present study was to validate twenty spatiotemporal gait parameters calculated by the WGAS by comparison with simultaneous measurements taken with an optical motion capture system (OMCS). METHODS: Ten young healthy volunteers wore two inertial sensors of the commercially available WGAS, Physilog®, on their feet and 23 markers for the OMCS on the lower part of the body. The participants performed at least three sets of 10-m walk tests at their self-paced speed in the laboratory equipped with 12 high-speed digital cameras with embedded force plates. To measure repeatability, all participants returned for a second day of testing within two weeks. RESULTS: Twenty gait parameters calculated by the WGAS had a significant correlation with the ones determined by the OMCS. Bland and Altman analysis showed that the between-device agreement for twenty gait parameters was within clinically acceptable limits. The validity of the gait parameters generated by the WGAS was found to be excellent except for two parameters, swing width and maximal heel clearance. The repeatability of the WGAS was excellent when measured between sessions. CONCLUSION: The present study showed that spatiotemporal gait parameters estimated by the WGAS were reasonably accurate and repeatable in healthy young adults, providing a scientific basis for applying this system to clinical studies.

Interplay between Inflammation and Pathological Bone Resorption: Insights into Recent Mechanisms and Pathways in Related Diseases for Future Perspectives.
M Alaa Terkawi, Gen Matsumae, Tomohiro Shimizu, Daisuke Takahashi, Ken Kadoya, Norimasa Iwasaki
International journal of molecular sciences, 23, 3, 2022年02月04日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Bone is a mineralized and elastic connective tissue that provides fundamental functions in the human body, including mechanical support to the muscles and joints, protection of vital organs and storage of minerals. Bone is a metabolically active organ that undergoes continuous remodeling processes to maintain its architecture, shape, and function throughout life. One of the most important medical discoveries of recent decades has been that the immune system is involved in bone remodeling. Indeed, chronic inflammation has been recognized as the most significant factor influencing bone homeostasis, causing a shift in the bone remodeling process toward pathological bone resorption. Bone osteolytic diseases typified by excessive bone resorption account for one of the greatest causes of disability worldwide, with significant economic and public health burdens. From this perspective, we discuss the recent findings and discoveries highlighting the cellular and molecular mechanisms that regulate this process in the bone microenvironment, in addition to the current therapeutic strategies for the treatment of osteolytic bone diseases.

Mature but not developing Schwann cells promote axon regeneration after peripheral nerve injury.
Takeshi Endo, Ken Kadoya, Tomoaki Suzuki, Yuki Suzuki, Mohamad Alaa Terkawi, Daisuke Kawamura, Norimasa Iwasaki
NPJ Regenerative medicine, 7, 1, 12, 12, 2022年01月28日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Since Schwann cells (SCs) support axonal growth at development as well as after peripheral nerve injury (PNI), developing SCs might be able to promote axon regeneration after PNI. The purpose of the current study was to elucidate the capability of developing SCs to induce axon regeneration after PNI. SC precursors (SCPs), immature SCs (ISCs), repair SCs (RSCs) from injured nerves, and non-RSCs from intact nerves were tested by grafting into acellular region of rat sciatic nerve with crush injury. Both of developing SCs completely failed to support axon regeneration, whereas both of mature SCs, especially RSCs, induced axon regeneration. Further, RSCs but not SCPs promoted neurite outgrowth of adult dorsal root ganglion neurons. Transcriptome analysis revealed that the gene expression profiles were distinctly different between RSCs and SCPs. These findings indicate that developing SCs are markedly different from mature SCs in terms of functional and molecular aspects and that RSC is a viable candidate for regenerative cell therapy for PNI.

Evaluation of biological responses to micro-particles derived from a double network hydrogel
Gen Matsumae, Mohamad Alaa Terkawi, Takayuki Nonoyama, Takayuki Kurokawa, Daisuke Takahashi, Tomohiro Shimizu, Ken Kadoya, Jian Ping Gong, Kazunori Yasuda, Norimasa Iwasaki
Biomaterials Science, Royal Society of Chemistry (RSC), 2022年, ［査読有り］
研究論文（学術雑誌）, Double network hydrogels have been proven to be a substitute biomaterial for cartilage. For further applications as articular cartilages, it is essential to understand the biological reactions that might be initiated by their micro-particles.

Cardiotrophin Like Cytokine Factor 1 (CLCF1) alleviates bone loss in osteoporosis mouse models by suppressing osteoclast differentiation through activating interferon signaling and repressing the nuclear factor-κB signaling pathway.
Shunichi Yokota, Gen Matsumae, Tomohiro Shimizu, Tomoka Hasegawa, Taku Ebata, Daisuke Takahashi, Cai Heguo, Yuan Tian, Hend Alhasan, Masahiko Takahata, Ken Kadoya, Mohamad Alaa Terkawi, Norimasa Iwasaki
Bone, 153, 116140, 116140, 2021年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, A growing body of evidence suggests that immune factors that regulate osteoclast differentiation and bone resorption might be promising therapeutic agents for the treatment of osteoporosis. The expression of CLCF1, an immune cell-derived molecule, has been reported to be reduced in patients with postmenopausal osteoporosis. This suggests that it may be involved in bone remodeling. Thus, we explored the functional role of CLCF1 in osteoclastogenesis and bone loss associated with osteoporosis. Surprisingly, the administration of recombinant CLCF1 repressed excessive bone loss in ovariectomized mice and prevented RANKL-induced bone loss in calvarial mouse model. Likewise, the addition of recombinant CLCF1 to RANKL-stimulated monocytes resulted in a significant suppression in the number of differentiated osteoclasts with small resorption areas being observed on dentine slices in vitro. At the same dosage, CLCF1 did not exhibit any detectable negative effects on the differentiation of osteoblasts. Mechanistically, the inhibition of osteoclast differentiation by the CLCF1 treatment appears to be related to the activation of interferon signaling (IFN) and the suppression of the NF-κB signaling pathway. Interestingly, the expression of the main components of IFN-signaling namely, STAT1 and IRF1, was detected in macrophages as early as 1 h after stimulation with CLCF1. Consistent with these results, the blockade of STAT1 in macrophages abolished the inhibitory effect of CLCF1 on osteoclast differentiation in vitro. These collective findings point to a novel immunoregulatory function of CLCF1 in bone remodeling and highlight it as a potentially useful therapeutic agent for the treatment of osteoporosis.

Association of gait with global cognitive function and cognitive domains detected by MoCA-J among community-dwelling older adults: a cross-sectional study.
Wen Hao, Wenjing Zhao, Takashi Kimura, Shigekazu Ukawa, Ken Kadoya, Katsunori Kondo, Akiko Tamakoshi
BMC geriatrics, 21, 1, 523, 523, 2021年10月02日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Gait was proved to be strongly associated with global cognitive function and multiple cognitive domains; however, previous research usually concentrated on individual gait parameters. This study used wearable sensors to measure gait parameters in different aspects and comprehensively explored the association of gait with global cognitive function and cognitive domains. METHODS: The data of this cross-sectional study were obtained from 236 community-dwelling Japanese older adults (125 men and 111 women) aged 70-81 years. Gait was measured by asking participants to walk a 6-m course and back using the Physilog® sensors (GaiUp®, Switzerland). Global cognitive function and cognitive domains were evaluated by face-to-face interviews using the Japanese version of the Montreal Cognitive Assessment. Twenty gait parameters were summarized as independent gait factors using factor analysis. A generalized linear model and linear regression model were used to explore the relationship of gait with global cognitive function and cognitive domains adjusted for several confounding factors. RESULTS: Factor analysis yielded four gait factors: general cycle, initial contact, propulsion, and mid-swing. Among them, general cycle factor was significantly associated with global cognitive function (β = - 0.487, [- 0.890, - 0.085]) and executive function (P = 0.049); initial contact was associated with executive function (P = 0.017). CONCLUSION: General cycle of gait might be the better marker of global cognitive function and gait is most strongly associated with executive function. The longitudinal relationships should be examined in future cohort studies.

Targeting thymidine phosphorylase as a potential therapy for bone loss associated with periprosthetic osteolysis.
Gen Matsumae, Tomohiro Shimizu, Yuan Tian, Daisuke Takahashi, Taku Ebata, Hend Alhasan, Shunichi Yokota, Ken Kadoya, Mohamad Alaa Terkawi, Norimasa Iwasaki
Bioengineering & translational medicine, 6, 3, e10232, 2021年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Macrophages are generally thought to play a key role in the pathogenesis of aseptic loosening through initiating periprosthetic inflammation and pathological bone resorption. The aim of this study was to identify macrophage-derived factors that promote osteoclast differentiation and periprosthetic bone destruction. To achieve this, we examined the effects of 12 macrophage-derived factors that were identified by RNA-seq analysis of stimulated macrophages on osteoclast differentiation. Surprisingly, thymidine phosphorylase (TYMP) was found to trigger significant number of osteoclasts that exhibited resorbing activities on dentine slices. Functionally, TYMP knockdown reduced the number of osteoclasts in macrophages that had been stimulated with polyethylene debris. TYMP were detected in serum and synovial tissues of patients that had been diagnosed with aseptic loosening. Moreover, the administration of TYMP onto calvariae of mice induced pathological bone resorption that was accompanied by an excessive infiltration of inflammatory cells and osteoclasts. The RNA-seq for TYMP-induced-osteoclasts was then performed in an effort to understand action mode of TYMP. TYMP stimulation appeared to activate the tyrosine kinase FYN signaling associated with osteoclast formation. Oral administration of saracatinib, a FYN kinase inhibitor, significantly suppressed formation of bone osteolytic lesions in a polyethylene debris-induced osteolysis model. Our findings highlight a novel molecular target for therapeutic intervention in periprosthetic osteolysis.

軸索再生に至適な移植細胞の同定を目的とした新しい末梢神経再建モデル
遠藤 健, 角家 健, 鈴木 裕貴, 河村 太介, 岩崎 倫政
北海道整形災害外科学会雑誌, 63, 1, 1, 13, 北海道整形災害外科学会, 2021年08月
日本語, 中枢神経と比較すると,末梢神経の再生能力は旺盛であるが,近位部損傷や重度損傷例では,軸索再生の量および速度が十分でないため,臨床成績は不良である.また,医療の発展にも関わらず,半世紀以上,自家神経移植に優る末梢神経再建方法はなく,自家組織を犠牲にせずに,軸索再生を促進する新規治療法の開発が望まれている.なかでも,近年の幹細胞研究の発展から,細胞治療に対する期待は大きい.しかし,軸索再生に至適な移植細胞は未だ明らかでない.今回,各種細胞の軸索再生効果の比較に有用な実験モデルを作成した.本モデルでは,野生型LEWISラットの坐骨神経に2ヶ所の圧挫損傷(25mm間隔)を作成し,続いて圧挫に挟まれた範囲の無細胞化のために液体窒素を用いた凍結融解処理を行った.作成したモデルの妥当性を検討するため,同系RFP発現ラットから採取したa)シュワン細胞(SC)またはb)骨髄間葉系間質細胞(Mesenchymal stromal cell:MSC)を移植し,対照群としてc)線維芽細胞(Fibroblast:Fb)移植,d)細胞移植なし,e)無細胞処置なし(圧挫単独)の3群を作成した.処置後2週の軸索再生はSC移植群で最も良好で,一方MSC,Fb移植群に軸索再生効果は認めず,移植細胞の軸索再生効果を明瞭に検出可能な実験モデルであった.興味深いことに,移植細胞の有無,種類に関わらず,無細胞野には宿主SCが遊走し,SCの分布量と再生軸索数には強い正の相関を認めた.さらには,全ての再生軸索にはSCが密接していた.これらの結果は末梢神経の再生過程にSCが極めて重要であることを示唆する所見であった.本モデルは,移植細胞の軸索再生効果の同定,および軸索再生効果の生物学的評価に有用な実験モデルであることが示された.(著者抄録)

Morphologic Changes in the Vertebral Artery Subsequent to Cervical Spine Degeneration and Aging: Analyses by Computed Tomography Angiography Using Multiplanar and 3-Dimensional Reconstructions
Takashi Ohnishi, Kota Suda, Miki Komatsu, Satoko Matsumoto Harmon, Takamasa Watanabe, Mitsuru Asukai, Ken Kadoya, Masahiko Takahata, Norimasa Iwasaki, Akio Minami
World Neurosurgery, 150, e686, e695, Elsevier BV, 2021年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: To identify the morphologic changes in the vertebral artery (VA) subsequent to cervical spine degeneration and aging and to investigate the risk factors for iatrogenic VA injury or occlusion. METHODS: Eighty-eight consecutive patients (176 bilateral VAs) were retrospectively analyzed using radiographs, computed tomography, and computed tomography angiography images. The Kellgren and Lawrence (KL) score and its modified subscores were used to grade the severity of degenerative changes in the cervical spine. VA tortuosity widths and diameters were measured between the C2 and C6 transverse foramens. The outcome measures were statistically analyzed for difference, correlation, and explanatory variable. The level with a high prevalence of VA stenosis was also evaluated. RESULTS: There were significant positive correlations between the KL score and VA tortuosity width, and between age and VA tortuosity width. Osteophyte formation in the facet joint was the predominant explanatory variable for medial deviation of the VA. Significant positive correlations were evident between the dominant VA diameter and KL score or age. VA stenosis occurred at C3/C4 (24.5%) with the highest prevalence and it was caused by uncovertebral joint osteophytes (52.0%) with the highest incidence. CONCLUSIONS: The present study provides important evidence for decisions of surgical strategy and for avoiding catastrophic VA injury or occlusion in cervical spine surgeries.

Flightless I is a catabolic factor of chondrocytes that promotes hypertrophy and cartilage degeneration in osteoarthritis
Taku Ebata, Mohamad Alaa Terkawi, Masanari Hamasaki, Gen Matsumae, Tomohiro Onodera, Mahmoud Khamis Aly, Shunichi Yokota, Hend Alhasan, Tomohiro Shimizu, Daisuke Takahashi, Kentaro Homan, Ken Kadoya, Norimasa Iwasaki
iScience, 102643, 102643, Elsevier BV, 2021年05月, ［査読有り］
研究論文（学術雑誌）

頸椎変性と加齢に伴い生じる椎骨動脈の形態的異常 術中椎骨動脈損傷と術後閉塞を回避するための新たなエビデンス
大西 貴士, 須田 浩太, 小松 幹, 松本 聡子, 渡辺 尭仁, 飛鳥井 光, 角家 健, 高畑 雅彦, 東條 泰明, 神谷 行宣, 岩崎 倫政, 三浪 明男
日本整形外科学会雑誌, 95, 3, S984, S984, (公社)日本整形外科学会, 2021年03月
日本語

末梢神経損傷後の好中球の時空間的変化に関する検討
山本 康弘, 角家 健, 岩崎 倫政, 市原 理司, 石島 旨章
北海道整形災害外科学会雑誌, 63, 139th suppl, 61, 61, 北海道整形災害外科学会, 2021年
日本語

Reference values for the locomotive syndrome risk test quantifying mobility of 8681 adults aged 20–89 years: A cross-sectional nationwide study in Japan
Keiko Yamada, Yoichi M. Ito, Masao Akagi, Etsuo Chosa, Takeshi Fuji, Kenichi Hirano, Shinichi Ikeda, Hideaki Ishibashi, Yasuyuki Ishibashi, Muneaki Ishijima, Eiji Itoi, Norimasa Iwasaki, Ryoichi Izumida, Ken Kadoya, Masayuki Kamimura, Arihiko Kanaji, Hiroyuki Kato, Shunji Kishida, Naohiko Mashima, Shuichi Matsuda, Yasumoto Matsui, Toshiki Matsunaga, Naohisa Miyakoshi, Hiroshi Mizuta, Yutaka Nakamura, Ken Nakata, Go Omori, Koji Osuka, Yuji Uchio, Kazuteru Ryu, Nobuyuki Sasaki, Kimihito Sato, Masuo Senda, Akihiro Sudo, Naonobu Takahira, Hiroshi Tsumura, Satoshi Yamaguchi, Noriaki Yamamoto, Kozo Nakamura, Takashi Ohe
Journal of Orthopaedic Science, 25, 6, 1084, 1092, Elsevier BV, 2020年11月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The locomotive syndrome risk test was developed to quantify the decrease in mobility among adults, which could eventually lead to disability. The purpose of this study was to establish reference values for the locomotive syndrome risk test for adults and investigate the influence of age and sex. METHODS: We analyzed 8681 independent community dwellers (3607 men, 5074 women). Data pertaining to locomotive syndrome risk test (the two-step test, the stand-up test, and the 25-question geriatric locomotive function scale [GLFS-25]) scores were collected from seven administrative areas of Japan. RESULTS: The reference values of the three test scores were generated and all three test scores gradually decreased among young-to-middle-aged individuals and rapidly decreased in individuals aged over 60 years. The stand-up test score began decreasing significantly from the age of 30 years. The trajectories of decrease in the two-step test score with age was slightly different between men and women especially among the middle-aged individuals. The two physical test scores were more sensitive to aging than the self-reported test score. CONCLUSION: The reference values generated in this study could be employed to determine whether an individual has mobility comparable to independent community dwellers of the same age and sex.

人工関節術後無菌性緩みにおけるチミジンホスホリラーゼの機能と骨吸収メカニズムの解明
松前 元, Terkawi Alaa, 木田 博朗, 江畑 拓, 田 園, Alhasan Hend, 清水 智弘, 高橋 大介, 角家 健, 岩崎 倫政
日本整形外科学会雑誌, 94, 8, S1711, S1711, (公社)日本整形外科学会, 2020年09月
日本語

Blockade of XCL1/Lymphotactin Ameliorates Severity of Periprosthetic Osteolysis Triggered by Polyethylene-Particles
Yuan Tian, Mohamad Alaa Terkawi, Tomohiro Onodera, Hend Alhasan, Gen Matsumae, Daisuke Takahashi, Masanari Hamasaki, Taku Ebata, Mahmoud Khamis Aly, Hiroaki Kida, Tomohiro Shimizu, Keita Uetsuki, Ken Kadoya, Norimasa Iwasaki
Frontiers in Immunology, 11, 1720, 1720, Frontiers Media SA, 2020年08月04日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Periprosthetic osteolysis induced by orthopedic implant-wear particles continues to be the leading cause of arthroplasty failure in majority of patients. Release of the wear debris results in a chronic local inflammatory response typified by the recruitment of immune cells, including macrophages. The cellular mediators derived from activated macrophages favor the osteoclast-bone resorbing activity resulting in bone loss at the site of implant and loosening of the prosthetic components. Emerging evidence suggests that chemokines and their receptors are involved in the progression of periprosthetic osteolysis associated with aseptic implant loosening. In the current study, we investigated the potential role of chemokine C-motif-ligand-1 (XCL1) in the pathogenesis of inflammatory osteolysis induced by wear particles. Expressions of XCL1 and its receptor XCR1 were evident in synovial fluids and tissues surrounding hip-implants of patients undergoing revision total hip arthroplasty. Furthermore, murine calvarial osteolysis model induced by ultra-high molecular weight polyethylene (UHMWPE) particles was used to study the role of XCL1 in the development of inflammatory osteolysis. Mice received single injection of recombinant XCL1 onto the calvariae after implantation of particles exhibited significantly greater osteolytic lesions than the control mice. In contrast, blockade of XCL1 by neutralizing antibody significantly reduced bone erosion and the number of bone-resorbing mature osteoclasts induced by UHMWPE particles. In consistence with the results, transplantation of XCL1-soaked sponge onto calvariae caused osteolytic lesions coincident with excessive infiltration of inflammatory cells and osteoclasts. These results suggested that XCL1 might be involved in the development of periprosthetic osteolysis through promoting infiltration of inflammatory cells and bone resorbing-osteoclasts. Our further results demonstrated that supplementing recombinant XCL1 to cultured human monocytes stimulated with the receptor activator of nuclear factor kappa-B ligand (RANKL) promoted osteoclastogenesis and the osteoclast-bone resorbing activity. Moreover, recombinant XCL1 promoted the expression of inflammatory and osteoclastogenic factors, including IL-6, IL-8, and RANKL in human differentiated osteoblasts. Together, these results suggested the potential role of XCL1 in the pathogenesis of periprosthetic osteolysis and aseptic loosening. Our data broaden knowledge of the pathogenesis of aseptic prosthesis loosening and highlight a novel molecular target for therapeutic intervention.

脊髄損傷治療の現状と脊髄再生-東京オリンピック、パラリンピックを記念して- 急性期病院が脊髄再生に果たすべき役割 つなぐべき希望
須田 浩太, 松本 聡子, 小松 幹, 大西 貴士, 渡辺 尭仁, 飛鳥井 光, 宇都宮 祥弘, 東條 泰明, 三浪 明男, 角家 健, 高畑 雅彦, 岩崎 倫政
日本整形外科学会雑誌, 94, 2, S26, S26, (公社)日本整形外科学会, 2020年03月
日本語

分化度の異なる各種シュワン細胞の末梢神経軸索再生効果の検討
遠藤 健, 角家 健, 鈴木 智亮, 松井 祐樹, 袁 儒非, 山本 康弘, 河村 太介, 岩崎 倫政
末梢神経, 30, 2, 257, 257, 日本末梢神経学会, 2019年12月
日本語

炎症収束性マクロファージ由来の新規骨吸収抑制因子の同定 骨粗鬆症に対する新たな治療法開発に向けて　　　　　　　　　　　　　　　
Terkawi M. Alaa, 松前 元, 田 園, Alhasan Hend, 濱崎 雅成, 江畑 拓, 高橋 大介, 角家 健, 岩崎 倫政
日本整形外科学会雑誌, 93, 8, S1834, S1834, (公社)日本整形外科学会, 2019年09月
日本語

Schwann細胞の接着因子を介した神経突起伸長効果の検討
遠藤 健, 角家 健, 鈴木 裕貴, 松居 祐樹, 袁 儒非, 鈴木 智亮, 福井 隆史, 山本 康弘, 河村 太介, 岩崎 倫政
日本整形外科学会雑誌, 93, 8, S1707, S1707, (公社)日本整形外科学会, 2019年09月
日本語

Evidence for cell-contact factor involvement in neurite outgrowth of DRG neurons stimulated by Schwann cells.
Endo T, Kadoya K, Kawamura D, Iwasaki N
Experimental physiology, 2019年07月, ［査読有り］, ［責任著者］

シュワン細胞の接着因子を介した神経突起伸長効果の検討　　　　　　　　　　　　　　　
遠藤 健, 角家 健, 松居 祐樹, 袁 儒非, 鈴木 智亮, 永野 裕介, 河村 太介, 岩崎 倫政
日本手外科学会雑誌, 36, 1, O3, 5, (一社)日本手外科学会, 2019年04月
日本語

軸索再生に至適なシュワン細胞の分化度に関する検討　　　　　　　　　　　　　　　
遠藤 健, 角家 健, 鈴木 智亮, 松居 祐樹, 袁 儒非, 永野 裕介, 河村 太介, 岩崎 倫政
日本手外科学会雑誌, 36, 1, BP2, 4, (一社)日本手外科学会, 2019年04月
日本語

Identification of IL-27 as potent regulator of inflammatory osteolysis associated with vitamin E-blended ultra-high molecular weight polyethylene debris of orthopedic implants.
Terkawi MA, Kadoya K, Takahashi D, Tian Y, Hamasaki M, Matsumae G, Alhasan H, Elmorsy S, Uetsuki K, Onodera T, Takahata M, Iwasaki N
Acta biomaterialia, 89, 242, 251, 2019年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Vitamin E-blended ultra-high molecular weight polyethylene (VE-UHMWPE) is a newly introduced material for prosthetic components that has proven a better mechanical performance with lesser adverse cellular responses than conventional polyethylene in experimental animal models. However, the mechanisms by which VE-UHMWPE particles trigger a reduced osteolytic activity are unclear and remain to be investigated. Therefore, the current study aims at exploring a possible anti-osteolytic mechanism associated with VE-UHMWPE particles. Transcriptional profiling and bioinformatic analyses of human macrophages stimulated by VE-UHMWPE particles revealed a distinct transcriptional program from macrophages stimulated with UHMWPE particles. Out of the up-regulated genes, IL-27 was found to be significantly elevated in macrophages cultured with VE-UHMWPE particles as compared to these with UHMWPE particles (p = 0.0084). Furthermore, we studied the potential anti-osteolytic function of IL-27 in osteolysis murine model. Interestingly, administration of recombinant IL-27 onto calvariae significantly alleviated osteolytic lesions triggered by UHMWPE particles (p = 0.0002). Likewise, IL-27 inhibited differentiation of osteoclasts (p = 0.0116) and reduced inflammatory response (p < 0.0001) elicited by conventional UHMWPE particles in vitro. This is the first study demonstrating the involvement of IL-27 in macrophage response to VE-UHMWPE particles and its regulatory role in osteolysis. Our data highlight a novel therapeutic agent for treatment of inflammatory osteolysis induced by polyethylene debris. STATEMENT OF SIGNIFICANCE: Aseptic loosening due to inflammatory osteolysis remains the major cause of arthroplasty failure and represents a substantial economic burden worldwide. Ideal approach to prevent this failure should be directed to minimize inflammatory response triggered by wear particles at the site of implant. Understanding the mechanism by which VE-UHMWPE particles triggers lesser cellular responses and reduced osteolysis as compared to conventional UHMWPE particles may aid in discovery of regulatory factors. In the current study, we reported that IL-27 is a potent regulator of inflammatory osteolysis involved in the reduced biologic activities and osteolytic potentials associated with VE-UHMWPE particles. Initiating the production IL-27 in vivo after total joint arthroplasties might be a novel strategy to prolong the life-spam of implant.

悪性腫瘍の脊椎直接浸潤に対する脊椎摘出術を行った症例について
岩田 玲, 高畑 雅彦, 須藤 英毅, 角家 健, 山田 勝久, 遠藤 努, 大西 貴士
北海道整形災害外科学会雑誌, 60, 2, 263, 263, 北海道整形災害外科学会, 2019年03月
日本語

合併症を生じやすい脊椎腫瘍手術の条件
岩田 玲, 高畑 雅彦, 角家 健, 須藤 英毅, 山田 勝久, 遠藤 努, 大西 貴士, 伊東 学, 鐙 邦芳, 岩崎 倫政
Journal of Spine Research, 10, 3, 272, 272, (一社)日本脊椎脊髄病学会, 2019年03月
日本語

Regenerating Corticospinal Axons Innervate Phenotypically Appropriate Neurons within Neural Stem Cell Grafts.
Kumamaru H, Lu P, Rosenzweig ES, Kadoya K, Tuszynski MH
Cell reports, 26, 9, 2329, 2339.e4, 2019年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Neural progenitor cell grafts form new relays across sites of spinal cord injury (SCI). Using a panel of neuronal markers, we demonstrate that spinal neural progenitor grafts to sites of rodent SCI adopt diverse spinal motor and sensory interneuronal fates, representing most neuronal subtypes of the intact spinal cord, and spontaneously segregate into domains of distinct cell clusters. Host corticospinal motor axons regenerating into neural progenitor grafts innervate appropriate pre-motor interneurons, based on trans-synaptic tracing with herpes simplex virus. A human spinal neural progenitor cell graft to a non-human primate also received topographically appropriate corticospinal axon regeneration. Thus, grafted spinal neural progenitor cells give rise to a variety of neuronal progeny that are typical of the normal spinal cord; remarkably, regenerating injured adult corticospinal motor axons spontaneously locate appropriate motor domains in the heterogeneous, developing graft environment, without a need for additional exogenous guidance.

炎症性骨溶解及び骨吸収におけるNOV(Nephroblastoma overexpressed)の機能解析
松前 元, テルカウィ・アラー, 田 園, 濱崎 雅成, ヘンド・アルハサン, 江畑 拓, 高橋 大介, 角家 健, 岩崎 倫政
北海道整形災害外科学会雑誌, 61, 136th suppl, 29, 29, 北海道整形災害外科学会, 2019年
日本語

シュワン細胞の接着因子を介した神経突起伸長効果の検討
遠藤 健, 角家 健, 鈴木 裕貴, 松居 祐樹, 袁 儒非, 鈴木 智亮, 福井 隆史, 山本 康弘, 河村 太介, 岩崎 倫政
北海道整形災害外科学会雑誌, 61, 136th suppl, 88, 88, 北海道整形災害外科学会, 2019年
日本語

転移性脊椎腫瘍術後合併症の危険因子
岩田 玲, 山田 勝久, 遠藤 努, 大西 貴士, 角家 健, 高畑 雅彦, 岩崎 倫政, 須藤 英毅
北海道整形災害外科学会雑誌, 61, 136th suppl, 8, 8, 北海道整形災害外科学会, 2019年
日本語

A Novel Experimental Model to Determine the Axon-Promoting Effects of Grafted Cells After Peripheral Nerve Injury.
Endo T, Kadoya K, Suzuki Y, Kawamura D, Iwasaki N
Frontiers in cellular neuroscience, 13, 280, 280, 2019年, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Although peripheral nerves can regenerate, clinical outcomes after peripheral nerve injuries are not always satisfactory, especially in cases of severe or proximal injuries. Further, autologous nerve grafting remains the gold standard for the reconstruction of peripheral nerves, although this method is still accompanied by issues of donor-site morbidity and limited supply. Cell therapy is a potential approach to overcome these issues. However, the optimal cell type for promoting axon regeneration remains unknown. Here, we report a novel experimental model dedicated to elucidation of the axon-promoting effects of candidate cell types using simple and standardized techniques. This model uses rat sciatic nerves and consists of a 25 mm-long acellular region and a crush site at each end. The acellular region was made by repeated freeze/thaw procedures with liquid nitrogen. Importantly, the new model does not require microsurgical procedures, which are technically demanding and greatly affect axon regeneration. To test the actual utility of this model, red fluorescent protein-expressing syngeneic Schwann cells (SCs), marrow stromal cells, or fibroblasts were grafted into the acellular area, followed by perfusion of the rat 2 weeks later. All types of grafted cells survived well. Quantification of regenerating axons demonstrated that SCs, but not the other cell types, promoted axon regeneration with minimum variability. Thus, this model is useful for differentiating the effects of various grafted cell types in axon regeneration. Interestingly, regardless of the grafted cell type, host SCs migrated into the acellular area, and the extent of axon regeneration was strongly correlated with the number of SCs. Moreover, all regenerating axons were closely associated with SCs. These findings suggest a critical role for SCs in peripheral nerve axon regeneration. Collectively, this novel experimental model is useful for elucidating the axon-promoting effects of grafted cells and for analyzing the biology of peripheral nerve axon regeneration.

分化度の異なる各種シュワン細胞の末梢神経軸索再生効果の検討
遠藤 健, 角家 健, 永野 裕介, 河村 大介, 岩崎 倫政
末梢神経, 29, 2, 253, 253, 日本末梢神経学会, 2018年12月
日本語

Injured adult motor and sensory axons regenerate into appropriate organotypic domains of neural progenitor grafts
Jennifer N. Dulin, Andrew F. Adler, Hiromi Kumamaru, Gunnar H. D. Poplawski, Corinne Lee-Kubli, Hans Strobl, Daniel Gibbs, Ken Kadoya, James W. Fawcett, Paul Lu, Mark H. Tuszynski
Nature Communications, 9, 1, 84, Nature Publishing Group, 2018年12月01日, ［査読有り］
英語, 研究論文（学術雑誌）, Neural progenitor cell (NPC) transplantation has high therapeutic potential in neurological disorders. Functional restoration may depend on the formation of reciprocal connections between host and graft. While it has been reported that axons extending out of neural grafts in the brain form contacts onto phenotypically appropriate host target regions, it is not known whether adult, injured host axons regenerating into NPC grafts also form appropriate connections. We report that spinal cord NPCs grafted into the injured adult rat spinal cord self-Assemble organotypic, dorsal horn-like domains. These clusters are extensively innervated by regenerating adult host sensory axons and are avoided by corticospinal axons. Moreover, host axon regeneration into grafts increases significantly after enrichment with appropriate neuronal targets. Together, these findings demonstrate that injured adult axons retain the ability to recognize appropriate targets and avoid inappropriate targets within neural progenitor grafts, suggesting that restoration of complex circuitry after SCI may be achievable.

Generation and post-injury integration of human spinal cord neural stem cells.
Kumamaru H, Kadoya K, Adler AF, Takashima Y, Graham L, Coppola G, Tuszynski MH
Nature methods, 15, 9, 723, 731, 2018年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Spinal cord neural stem cells (NSCs) have great potential to reconstitute damaged spinal neural circuitry, but they have yet to be generated in vitro. We now report the derivation of spinal cord NSCs from human pluripotent stem cells (hPSCs). Our observations show that these spinal cord NSCs differentiate into a diverse population of spinal cord neurons occupying multiple positions along the dorso-ventral axis, and can be maintained for prolonged time periods. Grafts into injured spinal cords were rich with excitatory neurons, extended large numbers of axons over long distances, innervated their target structures, and enabled robust corticospinal regeneration. The grafts synaptically integrated into multiple host intraspinal and supraspinal systems, including the corticospinal projection, and improved functional outcomes after injury. hPSC-derived spinal cord NSCs could enable a broad range of biomedical applications for in vitro disease modeling and constitute an improved clinically translatable cell source for 'replacement' strategies in several spinal cord disorders.

末梢神経の軸索再生はシュワン細胞の分布量と相関する
遠藤 健, 角家 健, 鈴木 裕貴, 岩崎 倫政
北海道整形災害外科学会雑誌, 60, 1, 143, 144, 北海道整形災害外科学会, 2018年08月
日本語

分化度の異なる各種Schwann細胞の末梢神経軸索再生効果の検討
遠藤 健, 角家 健, 鈴木 裕貴, 松居 祐樹, 袁 儒非, 永野 裕介, 河村 太介, 岩崎 倫政
日本整形外科学会雑誌, 92, 8, S1961, S1961, (公社)日本整形外科学会, 2018年08月
日本語

第5腰椎骨腫瘍摘出術における腸骨稜切離飜転による椎骨側方アプローチの有用性
岩田 玲, 高畑 雅彦, 須藤 英毅, 角家 健, 山田 勝久, 大西 貴士, 岩崎 倫政
東日本整形災害外科学会雑誌, 30, 3, 353, 353, 東日本整形災害外科学会, 2018年08月
日本語

Restorative effects of human neural stem cell grafts on the primate spinal cord
Ephron S Rosenzweig, John H Brock, Paul Lu, Hiromi Kumamaru, Ernesto A Salegio, Ken Kadoya, Janet L Weber, Justine J Liang, Rod Moseanko, Stephanie Hawbecker, J Russell Huie, Leif A Havton, Yvette S Nout-Lomas, Adam R Ferguson, Michael S Beattie, Jacqueline C Bresnahan, Mark H Tuszynski
Nature Medicine, 24, 4, 484, 490, Nature Publishing Group, 2018年05月01日, ［査読有り］
英語, 研究論文（学術雑誌）, We grafted human spinal cord-derived neural progenitor cells (NPCs) into sites of cervical spinal cord injury in rhesus monkeys (Macaca mulatta). Under three-drug immunosuppression, grafts survived at least 9 months postinjury and expressed both neuronal and glial markers. Monkey axons regenerated into grafts and formed synapses. Hundreds of thousands of human axons extended out from grafts through monkey white matter and synapsed in distal gray matter. Grafts gradually matured over 9 months and improved forelimb function beginning several months after grafting. These findings in a 'preclinical trial' support translation of NPC graft therapy to humans with the objective of reconstituting both a neuronal and glial milieu in the site of spinal cord injury.

AxonTracer: A novel ImageJ plugin for automated quantification of axon regeneration in spinal cord tissue
Akash Patel, Zhongzhi Li, Philip Canete, Hans Strobl, Jennifer Dulin, Ken Kadoya, Dan Gibbs, Gunnar H.D. Poplawski
BMC Neuroscience, 19, 1, 8, BioMed Central Ltd., 2018年03月09日, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Quantification of axon regeneration in spinal cord tissue sections is a fundamental step to adequately determine if an applied treatment leads to an anatomical benefit following spinal cord injury. Recent advances have led to the development of therapies that can promote regeneration of thousands of injured axons in vivo. Axon labeling methods and in the application of regeneration-enabling stem cell grafts have increased the number of detectable regenerating axons by orders of magnitudes. Manual axon tracing in such cases is challenging and laborious, and as such there is a great need for automated algorithms that can perform accurate tracing and quantification in axon-dense tissue sections. Results: We developed "AxonTracer", a fully automated software algorithm that traces and quantifies regenerating axons in spinal cord tissue sections. AxonTracer is an open source plugin for the freely available image-processing program ImageJ. The plugin identifies transplanted cells grafts or other regions of interest (ROIs) based on immunohistological staining and quantifies regenerating axons within the ROIs. Individual images or groups of images (batch mode) can be analyzed sequentially. In batch mode, a unique algorithm identifies a reference image for normalization, as well as a suitable image for defining detection parameters. An interactive user interface allows for adjustment of parameters defining ROI size, axon detection sensitivity and debris cleanup. Automated quantification of regenerating axons by AxonTracer correlates strongly with semi-manual quantification by the widely-used ImageJ plugin NeuronJ. However, quantification with AxonTracer is automated and reduces the need for user input compared to alternative methods. Conclusions: AxonTracer is a freely available open-source tool for automated analysis of regenerating axons in the injured nervous system. An interactive user interface provides detection-parameter adjustment, and usage does not require prior image analysis experience. Raw data as well as normalized results are stored in spreadsheet format and axon tracings are superimposed on raw images allowing for subjective visual verification. This software allows for automated, unbiased analysis of hundreds of axon-dense images, thus providing a useful tool in enabling in vivo screens of axon regeneration following spinal cord injury.

新規末梢神経軸索再生評価モデルが明らかにするシュワン細胞の軸索再生効果 骨髄間葉系幹細胞との比較
遠藤 健, 角家 健, 岩崎 倫政
北海道整形災害外科学会雑誌, 59, 2, 248, 249, 北海道整形災害外科学会, 2018年03月
日本語

分化度の異なる各種シュワン細胞の末梢神経軸索再生効果の検討
遠藤 健, 角家 健, 鈴木 裕貴, 松居 祐樹, 袁 儒非, 永野 裕介, 河村 太介, 岩崎 倫政
北海道整形災害外科学会雑誌, 60, 135th suppl, 23, 23, 北海道整形災害外科学会, 2018年
日本語

第5腰椎摘出術における脊柱起立筋付き腸骨 切離翻転による後方からの椎体側方剥離操作への有用性　　　　　　　　　　　　　　　
岩田 玲, 高畑 雅彦, 須藤 英毅, 角家 健, 山田 勝久, 遠藤 努, 大西 貴士, 岩崎 倫政
北海道整形災害外科学会雑誌, 60, 135th suppl, 70, 70, 北海道整形災害外科学会, 2018年
日本語

脊椎および骨盤への悪性腫瘍の直接浸潤に対する腫瘍全摘出術の報告　　　　　　　　　　　　　　　
岩田 玲, 高畑 雅彦, 須藤 英毅, 角家 健, 山田 勝久, 遠藤 努, 大西 貴士, 岩崎 倫政
北海道整形災害外科学会雑誌, 60, 135th suppl, 70, 70, 北海道整形災害外科学会, 2018年
日本語

Transcriptional profile of human macrophages stimulated by ultra-high molecular weight polyethylene particulate debris of orthopedic implants uncovers a common gene expression signature of rheumatoid arthritis
Mohamad Alaa Terkawi, Masanari Hamasaki, Daisuke Takahashi, Masahiro Ota, Ken Kadoya, Tomoyo Yutani, Keita Uetsuki, Tsuyoshi Asano, Tohru Irie, Ryuta Arai, Tomohiro Onodera, Masahiko Takahata, Norimasa Iwasaki
Acta Biomaterialia, 65, 417, 425, Acta Materialia Inc, 2018年01月01日, ［査読有り］
英語, 研究論文（学術雑誌）, Osteolysis is a serious postoperative complication of total joint arthroplasty that leads to aseptic loosening and surgical revision. Osteolysis is a chronic destructive process that occurs when host macrophages recognize implant particles and release inflammatory mediators that increase bone-resorbing osteoclastic activity and attenuate bone-formation osteoblastic activity. Although much progress has been made in understanding the molecular responses of macrophages to implant particles, the pathways/signals that initiate osteolysis remain poorly characterized. Transcriptomics and gene-expression profiling of these macrophages may unravel key mechanisms in the pathogenesis of osteolysis and aid the identification of molecular candidates for therapeutic intervention. To this end, we analyzed the transcriptional profiling of macrophages exposed to ultra-high molecular weight polyethylene (UHMWPE) particles, the most common components used in bearing materials of orthopedic implants. Regulated genes in stimulated macrophages were involved in cytokine, chemokine, growth factor and receptor activities. Gene enrichment analysis suggested that stimulated macrophages elicited common gene expression signatures for inflammation and rheumatoid arthritis. Among the regulated genes, tumor necrosis factor superfamily member 15 (TNFSF15) and chemokine ligand 20 (CCL20) were further characterized as molecular targets involved in the pathogenesis of osteolysis. Treatment of monocyte cultures with TNFSF15 and CCL20 resulted in an increase in osteoclastogenesis and bone-resorbing osteoclastic activity, suggesting their potential contribution to loosening between implants and bone tissues. Statement of Significance Implant loosening due to osteolysis is the most common mode of arthroplasty failure and represents a great challenge to orthopedic surgeons and a significant economic burden for patients and healthcare services worldwide. Bone loss secondary to a local inflammatory response initiated by particulate debris from implants is considered the principal feature of the pathogenesis of osteolysis. In the present study, we analyzed the transcriptional profiling of human macrophages exposed to UHMWPE particles and identified a large number of inflammatory genes that were not identified previously in macrophage responses to wear particles. Our data provide a new insight into the molecular pathogenesis of osteolysis and highlights a number of molecular targets with prognostic and therapeutic implications.

新規末梢神経再建モデルが明らかにした軸索再生におけるシュワン細胞の重要性
遠藤 健, 角家 健, 岩崎 倫政
末梢神経, 28, 2, 274, 274, 日本末梢神経学会, 2017年12月
日本語

Effective Repair of Dural Tear Using Bioabsorbable Sheet With Fibrin Glue
Akira Iwata, Masahiko Takahata, Ken Kadoya, Hideaki Sudo, Terufumi Kokabu, Katsuhisa Yamada, Norimasa Iwasaki
SPINE, 42, 18, 1362, 1366, LIPPINCOTT WILLIAMS & WILKINS, 2017年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Study Design. Basic science.
Objective. This study aimed to compare the techniques of surgical repair of dural tear using bioabsorbable material and fibrin glue.
Summary of Background Data. Cerebrospinal fluid (CSF) leakage caused by dural tear can often be difficult to manage even after repair when the same materials are used in a similar manner.
Methods. Burst pressure was measured for repaired porcine dura with holes of different diameters using spray of combined fibrinogen and thrombin solution (fibrin spray) alone as a control and the 5-mm hole following different methods using fibrinogen and thrombin solutions plus polyglactin 910 sheet (PGS). For group 1, fibrinogen was applied on the dura followed by PGS and thrombin. For group 2, thrombin was followed by PGS and fibrinogen. For group 3, fibrinogen was followed by PGS and fibrin spray. For group 4, thrombin was followed by PGS and fibrin spray. Microscopic observation was conducted for each specimen.
Results. Repair using fibrin spray alone was successful for the 0.3-mm diameter pinhole (breakdown pressure: 27.8 +/- 8.6 mmHg), but was not able to cover the 2.7-and 5-mm holes. For a 5-mm diameter hole, the breakdown pressure was 54.4 +/- 38.8 mmHg in group 1, 26.3 +/- 19.4 mmHg in group 2, 147.7 +/- 65.0 mmHg in group 3, and 35.5 +/- 23.4 mmHg in group 4 (P< 0.001). There was little fibrin glue in the burst layer between the dural surface and PGS with thrombin on the dural surface (group 2 and group 4).
Conclusion. Suppression of excessive CSF leakage could be successful by performing several cycles of the group 1 method (fibrinogen was applied on the dura followed by PGS and thrombin), followed by the group 3 method (fibrinogen was applied on the dura followed by PGS and fibrin spray), with thrombin solution wash each time.

In situ freeze and thaw法を用いた新しい末梢神経損傷モデル 軸索再生に至適な移植細胞同定のために
遠藤 健, 角家 健, 岩崎 倫政
北海道整形災害外科学会雑誌, 59, 1, 105, 105, 北海道整形災害外科学会, 2017年08月
日本語

新規末梢神経再建モデルが明らかにした軸索再生におけるSchwann細胞の重要性
遠藤 健, 角家 健, 鈴木 裕貴, 岩崎 倫政
日本整形外科学会雑誌, 91, 8, S1788, S1788, (公社)日本整形外科学会, 2017年08月
日本語

Comprehensive Monosynaptic Rabies Virus Mapping of Host Connectivity with Neural Progenitor Grafts after Spinal Cord Injury
Andrew F. Adler, Corinne Lee-Kubli, Hiromi Kumamaru, Ken Kadoya, Mark H. Tuszynski
STEM CELL REPORTS, 8, 6, 1525, 1533, CELL PRESS, 2017年06月, ［査読有り］
英語, 研究論文（学術雑誌）, Neural progenitor cells grafted to sites of spinal cord injury have supported electrophysiological and functional recovery in several studies. Mechanisms associated with graft-related improvements in outcome appear dependent on functional synaptic integration of graft and host systems, although the extent and diversity of synaptic integration of grafts with hosts are unknown. Using transgenic mouse spinal neural progenitor cell grafts expressing the TVA and G-protein components of the modified rabies virus system, we initiated monosynaptic tracing strictly from graft neurons placed in sites of cervical spinal cord injury. We find that graft neurons receive synaptic inputs from virtually every known host system that normally innervates the spinal cord, including numerous cortical, brainstem, spinal cord, and dorsal root ganglia inputs. Thus, implanted neural progenitor cells receive an extensive range of host neural inputs to the injury site, potentially enabling functional restoration across multiple systems.

In situ freeze and thaw法を用いた新しい末梢神経損傷モデル 軸索再生に至適な移植細胞同定のために
遠藤 健, 角家 健, 岩崎 倫政
末梢神経, 27, 2, 275, 275, 日本末梢神経学会, 2016年12月
日本語

In situ freeze and thaw法を用いた新しい末梢神経損傷モデル 軸索再生に至適な移植細胞同定のために
遠藤 健, 角家 健, 岩崎 倫政
日本整形外科学会雑誌, 90, 8, S1548, S1548, (公社)日本整形外科学会, 2016年08月
日本語

Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration
Ken Kadoya, Paul Lu, Kenny Nguyen, Corinne Lee-Kubli, Hiromi Kumamaru, Lin Yao, Joshua Knackert, Gunnar Poplawski, Jennifer N. Dulin, Hans Strob, Yoshio Takashima, Jeremy Biane, James Conner, Su-Chun Zhang, Mark H. Tuszynski
NATURE MEDICINE, 22, 5, 479, 487, NATURE PUBLISHING GROUP, 2016年05月, ［査読有り］
英語, 研究論文（学術雑誌）, The corticospinal tract (CST) is the most important motor system in humans, yet robust regeneration of this projection after spinal cord injury (SCI) has not been accomplished. In murine models of SCI, we report robust corticospinal axon regeneration, functional synapse formation and improved skilled forelimb function after grafting multipotent neural progenitor cells into sites of SCI. Corticospinal regeneration requires grafts to be driven toward caudalized (spinal cord), rather than rostralized, fates. Fully mature caudalized neural grafts also support corticospinal regeneration. Moreover, corticospinal axons can emerge from neural grafts and regenerate beyond the lesion, a process that is potentially related to the attenuation of the glial scar. Rat corticospinal axons also regenerate into human donor grafts of caudal spinal cord identity. Collectively, these findings indicate that spinal cord 'replacement' with homologous neural stem cells enables robust regeneration of the corticospinal projection within and beyond spinal cord lesion sites, achieving a major unmet goal of SCI research and offering new possibilities for clinical translation.

Axonal growth and connectivity from neural stem cell grafts in models of spinal cord injury
Paul Lu, Ken Kadoya, Mark H. Tuszynski
CURRENT OPINION IN NEUROBIOLOGY, 27, 103, 109, CURRENT BIOLOGY LTD, 2014年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Spinal cord injury (SCI) damages both gray matter and white matter, but white matter damage is responsible for the vast majority of the subsequent functional loss. Neural stem cells (NSCs). have been investigated as a means of improving outcomes after SCI, either through neuroprotective properties that limit secondary damage or by direct cell replacement. This review will focus on cell replacement strategies, and the ability of multipotent NSCs to form new functional synaptic relays across sites of even severe SCI. The ability of these early stage neurons to extend axons from the lesion site in large numbers and over long distances constitutes an important mechanism underlying their potential to promote neural repair.

Combined Intrinsic and Extrinsic Neuronal Mechanisms Facilitate Bridging Axonal Regeneration One Year after Spinal Cord Injury
Ken Kadoya, Shingo Tsukada, Paul Lu, Giovanni Coppola, Dan Geschwind, Marie T. Filbin, Armin Blesch, Mark H. Tuszynski
NEURON, 64, 2, 165, 172, CELL PRESS, 2009年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Despite advances in promoting axonal regeneration after acute spinal cord injury (SCI), elicitation of bridging axon regeneration after chronic SCI remains a formidable challenge. We report that combinatorial therapies administered 6 weeks, and as long as 15 months, after SCI promote axonal regeneration into and beyond a midcervical lesion site. Provision of peripheral nerve conditioning lesions, grafts of marrow stromal cells, and establishment of NT-3 gradients supports bridging regeneration. Controls receiving partial components of the full combination fail to exhibit bridging. Notably, intraneuronal molecular mechanisms recruited by delayed therapies mirror those of acute injury, including activation of transcriptional activators and regeneration-associated genes. Collectively, these findings provide evidence that regeneration is achievable at unprecedented postinjury time points.

Efficient retrograde neuronal transduction utilizing self-complementary AAV1
Edmund R. Hollis, Ken Kadoya, Matthew Hirsch, Richard J. Samulski, Mark H. Tuszynski
MOLECULAR THERAPY, 16, 2, 296, 301, NATURE PUBLISHING GROUP, 2008年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Adeno-associated virus (AAV) is frequently used for gene transfer into the central nervous system (CNS). Similar to adenovirus and rabies virus, AAV can be taken up by axons and retrogradely transported, resulting in neuronal gene expression distant from the injection site. We investigated the retrograde transport properties of self-complementary AAV (scAAV) serotypes 1 - 6 following peripheral injection. Injection of scAAV into either rat extensor carpi muscle or sciatic nerve resulted in detectable retrograde vector transport and reporter gene expression in spinal cord motor neurons (MNs). Serotype 1 resulted in the highest level of retrograde transport, with 4.1 +/- 0.3% of cervical MNs projecting to the extensor carpi transduced following intramuscular injection, and 7.5 +/- 3.1% of lumbar MNs transduced after sciatic nerve injection. In contrast to scAAV1, retrograde transduction with scAAV2 was undetectable following intramuscular injection, and was detected in only 0.81 +/- 0.15% of MNs projecting to the sciatic nerve following intranerve injection. Furthermore, sciatic injection of single-stranded AAV1 required injection of tenfold higher numbers of viral particles for detectable transgene expression compared to scAAV1, and then only 0.91 +/- 0.24% of lumbar MNs were transduced. Our data provide the basis for increased retrograde transduction efficiency using peripheral injections of scAAV1 vectors for therapeutic gene delivery to the spinal cord.

Efficient retrograde neuronal transduction utilizing self-complementary AAV1
Edmund R. Hollis, Ken Kadoya, Matthew Hirsch, Richard J. Samulski, Mark H. Tuszynski
MOLECULAR THERAPY, 16, 2, 296, 301, NATURE PUBLISHING GROUP, 2008年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Adeno-associated virus (AAV) is frequently used for gene transfer into the central nervous system (CNS). Similar to adenovirus and rabies virus, AAV can be taken up by axons and retrogradely transported, resulting in neuronal gene expression distant from the injection site. We investigated the retrograde transport properties of self-complementary AAV (scAAV) serotypes 1 - 6 following peripheral injection. Injection of scAAV into either rat extensor carpi muscle or sciatic nerve resulted in detectable retrograde vector transport and reporter gene expression in spinal cord motor neurons (MNs). Serotype 1 resulted in the highest level of retrograde transport, with 4.1 +/- 0.3% of cervical MNs projecting to the extensor carpi transduced following intramuscular injection, and 7.5 +/- 3.1% of lumbar MNs transduced after sciatic nerve injection. In contrast to scAAV1, retrograde transduction with scAAV2 was undetectable following intramuscular injection, and was detected in only 0.81 +/- 0.15% of MNs projecting to the sciatic nerve following intranerve injection. Furthermore, sciatic injection of single-stranded AAV1 required injection of tenfold higher numbers of viral particles for detectable transgene expression compared to scAAV1, and then only 0.91 +/- 0.24% of lumbar MNs were transduced. Our data provide the basis for increased retrograde transduction efficiency using peripheral injections of scAAV1 vectors for therapeutic gene delivery to the spinal cord.

Effect of Hydroxyapatite porous characteristics on healing outcomes in rabbit posterolateral spinal fusion model
Makoto Motomiya, Manabu Ito, Masahiko Takahata, Ken Kadoya, Kazuharu Irie, Kuniyoshi Abumi, Akio Minami
EUROPEAN SPINE JOURNAL, 16, 12, 2215, 2224, SPRINGER, 2007年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Hydroxyapatite (HA) has been commonly used as a bone graft substitute in various kinds of clinical fields. To improve the healing capability of HA, many studies have been performed to reveal its optimal structural characteristics for better healing outcomes. In spinal reconstruction surgery, non-interconnected porous HAs have already been applied as a bone graft extender in order to avoid autogenous bone harvesting. However, there have been few experimental studies regarding the effects of the structural characteristics of HA in posterolateral lumbar intertransverse process spine fusion (PLF). The aims of this study were to investigate the effect of HA porous characteristics on healing outcomes in a rabbit PLF model in order to elucidate appropriate structural characteristics of HA as a bone graft extender. Thirty-six adult female Japanese White rabbits underwent bilateral intertransverse process fusion at the level of L5-6 without internal fixation. We prepared three types of HA with different porosities: HA with 15% porosity (HA15%), HA with 50% porosity (HA50%), and HA with 85% porosity (HA85%), all of which were clinically available materials. The HA15% and HA50% had few interconnecting pores, whereas the HA85%, which was a recently developed material, had abundant interconnecting pores. All rabbits were randomly divided into the following four groups according to the grafted materials: (1) HA15% + autogenous bone, (2) HA50% + autogenous bone, (3) HA85% + autogenous bone, (4) pure autogenous bone graft. The animals were euthanized at 5 weeks after surgery, and post-mortem analyses including biomechanical testing, radiographical and histological evaluations were performed. There was no statistically significant difference in either fusion rate and/or bending stiffness among the three HA groups. However, in histological and radiological analyses, both bone ingrowth rate and direct bone bonding rate in the HA85% group were significantly higher than those in the HA15% and HA50% groups, despite the similar value of bone volume rate in fusion mass among the three HA groups. In the HA85% group, bone ingrowth was achieved throughout the implanted HAs via interconnecting pores and there was excellent unification between the HA granules and the newly mineralized bone. On the other hand, in the non-interconnected porous HA groups, only a little bone ingrowth could be seen at the peripheral pores of the implanted HA, and its surface was mostly covered with fibrous tissue or empty space. The current study demonstrated that the HA porous characteristics had an effect on the histological outcomes in a rabbit PLF model. We would like to conclude that the interconnected high porous structure seems to be promising for the environment of PLF in the point of producing fusion mass with higher cellular viability. This is because the HA85% is superior in terms of integration with the newly formed bone in fusion mass compared to the non-interconnected porous HAs. However, the porous modifications of HA have little influence on fusion rate and mechanical strength because primary stabilization of the fusion segment is mainly achieved by bridging bone between the adjacent transverse processes outside the implanted materials, rather than the degree of integration between the newly formed bone and the HA granules in PLF.

Clinical outcome of posterolateral endoscopic surgery for pyogenic spondylodiscitis - Results of 15 patients with serious comorbid conditions
Manabu Ito, Kuniyoshi Abumi, Yoshihisa Kotani, Ken Kadoya, Akio Minami
SPINE, 32, 2, 200, 206, LIPPINCOTT WILLIAMS & WILKINS, 2007年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Study Design. Clinical results of posterolateral endoscopic debridement and irrigation followed by percutaneous drainage for pyogenic spondylodiscitis were analyzed.
Objectives. To report clinical results of transforaminal endoscopic surgery for pyogenic spondylodiscitis and to evaluate the effectiveness of this procedure in treatment of pyogenic spinal infections.
Summary of Background Data. Pyogenic spinal infections have been increasing due to the development of medical treatment for patients with comorbid medical problems. Common treatments for spinal infections are administration of antibiotics or surgical debridement with bone grafts. There have been no reports, however, regarding the clinical outcome of posterolateral endoscopic treatment for pyogenic spinal infections.
Methods. Fifteen consecutive patients with pyogenic spondylodiscitis in the thoracic or lumbar spine were enrolled. Preoperative antibiotic treatment had failed in all the patients. The procedures consisted of posterolateral endoscopic debridement and irrigation followed by percutaneous drainage through single portal under the combination of local and intravenous anesthesia. Pain response using visual analog scale (VAS, 0-100 mm), inflammation parameters, and duration of antibiotic therapy were investigated. Radiologic evaluation focused on bony fusion, local kyphosis, disc height reduction, and abscess formation.
Results. All patients showed immediate pain reduction after surgery. Averaged VAS for pain was 86 before surgery and 25 at postoperative 1 week. Average of CRP was 4.00 mg/dL before surgery and 1.88 mg/dL at postoperative 1 week. Averaged duration of antibiotics therapy was 3.7 weeks. Spinal fusion was obtained in 13 patients. Two patients with neurologic deficits due to epidural abscess returned to normal. Preoperative psoas abscess in 6 patients disappeared after surgery on MRI.
Conclusions. Posterolateral spinal endoscopic debridement and irrigation brought immediate pain reduction and good clinical results to patients who had comorbid medical problems and had pyogenic spondylodiscitis.

Vertebral osteonecrosis associated with sarcoidosis - Case report
M Ito, M Motomiya, K Abumi, O Shirado, Y Kotani, K Kadoya, E Murota, A Minami
JOURNAL OF NEUROSURGERY-SPINE, 2, 2, 222, 225, AMER ASSOC NEUROLOGICAL SURGEONS, 2005年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Sarcoidosis is a systemic disease commonly affecting lung, skin, or eye. Sarcoidosis involved with osseous structures occurs in approximately 5% of patients, usually involving small bones. Spinal sarcoidosis is extremely rare. The authors report on a man in whom examination of a subclavicular lymph node biopsy specimen and its spinal involvement had established a diagnosis of sarcoidosis and who had undergone steroid therapy. Despite intensive conservative treatment, the authors observed progressive collapse of L-2 requiring spinal decompressive and reconstructive surgeries. Histological evaluation of the collapsed vertebra did not show the typical noncaseating granuloma; rather, the authors observed osteonecrosis of the entire L-2 structure without reactive cellular activities, Other potential diagnoses including infectious disease, metastatic spinal tumor, and osteoporotic vertebral collapse were excluded based on laboratory data, imaging studies, and pathological findings. Complete necrosis of the entire L-2 vertebra in this case can be considered as a rare clinical manifestation of spinal sarcoidosis. Because of osteopenia and systemic bone fragility, combined anterior-posterior spinal reconstructive surgery was performed to restabilize the severely damaged Spine.

Vertebral osteonecrosis associated with sarcoidosis. Case report.
Ito M, Motomiya M, Abumi K, Shirado O, Kotani Y, Kadoya K, Murota E, Minami A
Journal of neurosurgery. Spine, 2, 2, 222, 225, 2005年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Sarcoidosis is a systemic disease commonly affecting lung, skin, or eye. Sarcoidosis involved with osseous structures occurs in approximately 5% of patients, usually involving small bones. Spinal sarcoidosis is extremely rare. The authors report on a man in whom examination of a subclavicular lymph node biopsy specimen and its spinal involvement had established a diagnosis of sarcoidosis and who had undergone steroid therapy. Despite intensive conservative treatment, the authors observed progressive collapse of L-2 requiring spinal decompressive and reconstructive surgeries. Histological evaluation of the collapsed vertebra did not show the typical noncaseating granuloma; rather, the authors observed osteonecrosis of the entire L-2 structure without reactive cellular activities. Other potential diagnoses including infectious disease, metastatic spinal tumor, and osteoporotic vertebral collapse were excluded based on laboratory data, imaging studies, and pathological findings. Complete necrosis of the entire L-2 vertebra in this case can be considered as a rare clinical manifestation of spinal sarcoidosis. Because of osteopenia and systemic bone fragility, combined anterior-posterior spinal reconstructive surgery was performed to restabilize the severely damaged spine.

Two-year observation of artificial intervertebral disc replacement: results after supplemental ultra-high strength bioresorbable spinal stabilization
Y Kotani, K Abumi, Y Shikinami, M Takahata, K Kadoya, T Kadosawa, A Minami, K Kaneda
JOURNAL OF NEUROSURGERY, 100, 4, 337, 342, AMER ASSOC NEUROLOGICAL SURGEONS, 2004年04月, ［査読有り］
英語, 研究論文（学術雑誌）, Object. This 2-year experimental study was conducted to investigate the efficacy of a bioactive three-dimensional (3D) fabric disc for lumbar intervertebral disc replacement. The authors used a bioresorbable spinal fixation rod consisting of a forged composite of particulate unsintered hydroxyapatite/poly-L-lactide acid (HA/PLLA) for stability augmentation. The biomechanical and histological alterations as well as possible device-related loosening were examined at 2 years postoperatively.
Methods. Two lumbar intervertebral discs (L2-3 and L4-5) were replaced with the 3D fabric discs, which were augmented by two titanium screws and a spanning bioresorbable rod (HA/PLLA). The segmental biomechanics and interface bone ingrowth were investigated at 6, 15, and 24 months postoperatively, and results were compared with the other two surgical groups (3D fabric disc alone; 3D fabric disc with additional anterior instrumentation stabilization). The 3D fabric disc and HA/PLLA-spinal segments demonstrated segmental mobility at 15 and 24 months; however, the range of motion (ROM) in flexion-extension decreased to 49 and 40%, respectively, despite statistically equivalent preserved torsional ROM. Histologically there was excellent osseous fusion at the 3D fabric disc surface-vertebral body interface. At 2 years posttreatment, no adverse tissue reaction nor aseptic loosening of the device was observed.
Conclusions. Intervertebral disc replacement with the 3D fabric disc was viable and when used in conjunction with the bioresorbable HA/PLLA spinal augmentation. Further refinements of device design to create a stand-alone type are necessary to obviate the need for additional spinal stabilization.

Static and dynamic analysis of five anterior instrumentation systems for thoracolumbar scoliosis
N Shimamoto, Y Kotani, Y Shono, K Kadoya, K Abumi, A Minami, K Kaneda
SPINE, 28, 15, 1678, 1685, LIPPINCOTT WILLIAMS & WILKINS, 2003年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Study Design. A nondestructive biomechanical investigation among five anterior spinal instrumentation systems for scoliosis.
Objectives. The purpose of this study is to analyze the static and dynamic biomechanical stability of five different systems.
Summary of Background Data. Although a variety of anterior spinal instrumentation systems for scoliosis are available, very few attempts have been made at comparative biomechanical studies.
Methods. Thirty calf spines were underwent static biomechanical tests, including flexion - extension, axial rotation, and lateral bending loading modes in the multisegmental spinal model. Five anterior instrumentation systems included: 1) Texas Scottish Rite Hospital system; 2) Bad Wildungen Metz; 3) anterior ISOLA; 4) Cotrel Dubousset Hoph; and 5) Kaneda Anterior Scoliosis System. The initial and postfatigue stability after a cyclic loading test were analyzed by measuring the range of motion at instrumented segments compared to the intact within the same specimen (% to intact).
Results. Two-rod systems showed a significant decrease in range of motion compared to one-rod systems in flexion - extension ( P < 0.001) and axial rotation ( P < 0.05). In lateral bending, all systems demonstrated a significant decrease in range of motion of less than 40% to the intact ( P < 0.001). After cyclical loading test, all systems increased in range of motion. In flexion - extension, one-rod systems depicted a significant increase in range of motion, compared to two-rod systems ( P < 0.05).
Conclusions. In the initial stability analysis, two-rod systems are superior to one-rod systems. For one-rod systems, repeated physiologic loading may result in reduced stability in flexion - extension.

Artificial intervertebral disc replacement using bioactive three-dimensional fabric - Design, development, and preliminary animal study
Y Kotani, K Abumi, Y Shikinami, T Takada, K Kadoya, N Shimamoto, M Ito, T Kadosawa, T Fujinaga, K Kaneda
SPINE, 27, 9, 929, 935, LIPPINCOTT WILLIAMS & WILKINS, 2002年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Study Design. A new artificial intervertebral disc was developed, and its intrinsic biomechanical properties, bioactivity, and the effectiveness as a total disc replacement were evaluated in vitro and in vivo.
Objectives. To introduce a new artificial intervertebral disc and to evaluate the in vitro mechanical properties, fusion capacity to bone, and segmental biomechanics in the total intervertebral disc replacement using a sheep lumbar spine.
Summary of Background Data. The loss of biologic fusion at the bone-implant interface and prosthetic failures have been reported in previous artificial discs. There have been no clinically applicable discs with detailed experimental testing of in vivo mechanics and interface fusion capacity.
Methods. The artificial intervertebral disc consists of a triaxial three-dimensional fabric (3-DF) woven with an ultra-high molecular weight polyethylene fiber, and spray-coated bioactive ceramics on the disc surface. The arrangement of weave properties was designed to produce mechanical behavior nearly equivalent to the natural intervertebral disc. Total intervertebral disc replacement at L2-L3 and L4-L5 was performed using 3-DF disc with or without internal fixation in a sheep lumbar spine model. The segmental biomechanics and interface histology were evaluated after surgery at 4 and 6 months.
Results. The tensile-compressive and torsional properties of prototype 3-DF were nearly equivalent to those of human lumbar disc. The lumbar segments replaced with 3-DF disc alone showed a significant decrease of flexion-extension range of motion to 28% of control values as well as partial bony fusion at 6 months. However, the use of temporary fixation provided a nearly physiologic mobility of the spinal segment after implant removal as well as excellent bone-disc fusion at 6 months.
Conclusion. An artificial intervertebral disc using a three-dimensional fabric demonstrated excellent in vitro and in vivo performance in both biomechanics and interface histology. There is a potential for future clinical application.

Biomechanical evaluation of anterior spinal instrumentation systems for scoliosis - In vitro fatigue simulation
N Shimamoto, Y Kotani, Y Shono, K Kadoya, K Abumi, K Kaneda, A Minami
SPINE, 26, 24, 2701, 2708, LIPPINCOTT WILLIAMS & WILKINS, 2001年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Study Design. A biomechanical study was designed to assess the bone-screw interface fixation strength among five anterior spinal instrumentation systems for scoliosis before and after a fatigue simulation.
Objectives. The objectives of the current study were twofold: 1) evaluate the static (initial) strength at the bone-screw interface and 2) evaluate dynamic (post fatigue) strength of the bone-screw interface after a fatigue simulation to investigate a possible mechanism for postoperative loss of correction.
Summary of Background Data. Although the recent advancement of anterior instrumentation for scoliosis has permitted shorter fusion segments and improved surgical correction, the loss of correction over the instrumented segments still has been reported in one-rod systems. Little is known about the mechanism for loss of correction.
Methods. Twenty-five fresh-frozen calf spines (T6-L6) were used. A total of five instrumentation systems included the following: Anterior ISOLA (ISOLA), Bad Wildungen Metz (BWM), Texas Scottish Rite Hospital system (TSRH), Cotrel-Dubousset Hoph (CDH), and Kaneda Anterior Scoliosis System (KASS). Screw pullout and rotational tests in the sagittal plane using a single vertebra were performed to investigate bone-screw interface fixation strength before and after a fatigue simulation. To simulate cyclic loading that the spine could undergo in vivo, a fatigue simulation using compressive-flexion loading up to 24,000 cycles was carried out.
Results. Mean maximum tensile pullout force decreased in the following order: KASS > CDH > BWM > TSRH > ISOLA (F = 29 91, P < 0.0001). KASS blunt tip screw was 26% stronger in pullout force than KASS sharp tip screw (P < 0.05). The one-rod system demonstrated a positive correlation between pullout force and both bone mineral density and screw insertional torque, For fatigue analysis the rotational strength at the most cephalad and caudal segments significantly decreased after a fatigue simulation in the one-rod system (P < 0.05). The two-rod system showed no significant decrease after a fatigue simulation.
Conclusions. Simulating the cyclic loading to the construct, screw loosening at the bone-screw interface was produced in the one-rod system, This screw loosening may elucidate one mechanism for loss of correction in the one-rod system. The two-rod system may have the potential to minimize the risk of loss of correction.

Biomechanical and morphologic evaluation of a three-dimensional fabric sheep artificial intervertebral disc - In vitro and in vivo analysis
K Kadoya, Y Kotani, K Abumi, T Takada, N Shimamoto, Y Shikinami, T Kadosawa, K Kaneda
SPINE, 26, 14, 1562, 1569, LIPPINCOTT WILLIAMS & WILKINS, 2001年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Study Design. We have developed a new artificial intervertebral disc consisting of triaxial three-dimensional fabric for the sheep lumbar spine. To clarify the characteristics of the new implant, a series of biomechanical tests and morphologic evaluations were conducted.
Objectives. To investigate the static, viscoelastic, and fatigue properties of the three-dimensional fabric disc in comparison with natural sheep disc and to evaluate their biomechanical and morphologic alteration in vivo.
Summary of Background Data. In its human dimensions the three-dimensional fabric disc revealed mechanical properties similar to a natural human disc.
Methods. The disc-body units from sheep spine and the sheep three-dimensional fabric discs underwent tensile-compressive (200 N), torsional (5 Nm), and creep-recovery tests (30 minutes-30 minutes, 200 N). After fatigue loading (2 million, compressive 200 N) the biomechanical changes and the debris were investigated. For in vivo evaluation after placing in the sheep psoas muscles for 6 months, the surface of the three-dimensional fabric disc was evaluated using macroscopy and scanning electron microscopy, followed by previous biomechanical tests.
Results. The behavior of the sheep three-dimensional fabric disc was similar to that of natural sheep disc in tensile-compressive and creep-recovery tests. In torsional testing the behavior of natural sheep disc was more rigid than that of the sheep three-dimensional fabric disc. After fatigue loading there was no biomechanical change and no debris detected. Six months after surgery no morphologic deterioration was observed nor were there changes in biomechanical parameters.
Conclusions. The sheep three-dimensional fabric disc exhibited biomechanical and morphologic biostability, appropriate viscoelasticity, and excellent fatigue properties. The three-dimensional fabric disc has a potential far clinical application of human intervertebral disc-replacement.

骨格情報と人工知能を活用した新規歩行解析方法-膝前十字靱帯損傷の鑑別-
宝満健太郎, 角家健, 三宅賢稔, 三宅賢稔, 三谷雄輝, 石田直樹, 堀脇一樹, 中川弘充, 田中毅, 片岸誠, 禰寝義人, 禰寝義人, 岩崎倫政, 日本整形外科学会雑誌, 98, 2, 2024年

足部ウェアラブルデバイスによる歩行解析の妥当性と臨床研究の実際
角家健, 宝満健太郎, 岩崎倫政, 日本臨床スポーツ医学会誌, 31, 4, 2023年

深度カメラと機械学習の応用による全身を対象とした歩行解析-前十字靱帯再建術後の歩行識別の試み-
宝満健太郎, 角家健, 三宅賢稔, 三宅賢稔, 浮城健吾, 福井大輔, 中川弘充, 田中毅, 片岸誠, 大越康充, 禰寝義人, 岩崎倫政, 日本整形外科学会雑誌, 97, 8, 2023年

全身を対象とした動作解析によるACL再建者の歩行識別:深度カメラと機械学習の応用
宝満健太郎, 岩崎倫政, 角家健, 三宅賢稔, 三宅賢稔, 片岸誠, 禰寝義人, 浮城健吾, 井上貴博, 大越康充, 福井大輔, 中川弘充, 田中毅, 北海道整形災害外科学会, 142nd, 2023年

歩行撮影とAIを使用した変形性膝関節症の新規診断方法の開発
角家健, 宝満健太郎, 三宅賢稔, 三宅賢稔, 浮城健吾, 福井大輔, 中川弘充, 田中毅, 深水竜介, 大越康充, 禰寝義人, 岩崎倫政, 日本整形外科学会雑誌, 97, 2, 2023年

歩行撮影と機械学習を使用した変形性膝関節症の新規診断方法の開発
角家健, 宝満健太郎, 三宅賢稔, 三宅賢稔, 浮城健吾, 福井大輔, 中川弘充, 田中毅, 深水竜介, 大越康充, 禰寝義人, 岩崎倫政, 日本整形外科学会雑誌, 96, 8, 2022年

足部ウェアラブルデバイスによる歩行解析の妥当性と臨床研究の実際
角家健, 宝満健太郎, 岩崎倫政, 日本関節病学会誌(Web), 41, 3, 2022年

歩行撮影とAIを使用した運動器疾患診断方法の開発
角家健, 宝満健太郎, 三宅賢稔, 三宅賢稔, 浮城健吾, 福井大輔, 中川弘充, 田中毅, 深水竜介, 大越康充, 禰寝義人, 岩崎倫政, 日本骨代謝学会学術集会プログラム抄録集(CD-ROM), 40th, 2022年

歩行撮影とAIを使用した変形性膝関節症の新規診断方法の開発
角家健, 三宅賢稔, 宝満健太郎, 岩崎倫政, 三宅賢稔, 深水竜介, 禰寝義人, 浮城健吾, 大越康充, 福井大輔, 中川弘, 田中毅, 北海道整形災害外科学会, 141st, 2022年

変形性膝関節症の新規スクリーニング方法の開発-歩行撮影による歩行解析-
角家健, 宝満健太郎, 浮城健吾, 三宅賢稔, 三宅賢稔, 深水竜介, 禰寝義人, 大越康充, 岩崎倫政, 日本整形外科学会雑誌, 96, 2, 2022年

歩行動画によるロコモ評価システムの開発
角家健, 山本強, 宝満健太郎, 岩崎倫政, 医科学応用研究財団研究報告(CD-ROM), 38, 2021年

歩行解析研究に汎用される10m直線歩行は普段の歩行を代表しているか-足部時空間パラメーターによる検討-
角家健, 種田健二, 宝満健太郎, 須田浩太, 松本聡子, 石田直樹, 武田直樹, 大越康充, 大野和則, 菅原誠, 三浪明男, 岩崎倫政, 日本整形外科学会雑誌, 95, 2, 2021年

歩行解析研究に汎用される10m直線歩行は普段の歩行を代表しているか?:足部時空間パラメータによる検討
角家健, 宝満健太郎, 岩崎倫政, 種田健二, 須田浩太, 松本聡子, 三浪明男, 石田直樹, 武田直樹, 大越康充, 大野和則, 菅原誠, 北海道整形災害外科学会, 139th, 2021年

片麻痺患者の杖歩行時の足部時空間パラメータに関する検討
宝満健太郎, 角家健, 斉藤貴志, 佐伯拓馬, 石田直樹, 岩崎倫政, 運動器リハビリテーション, 30, 2, 195, 195, 2019年06月06日
日本運動器科学会, 日本語

Validation of the Wearable Sensor System Estimating Spatiotemporal Gait Parameters by Simultaneous 3D Optical Motion Analysis.　　　　　　　　　　　　　　　
Kentaro Homan, Ken Kadoya, Keizo Yamamoto, Norimasa Iwasaki, The 65th Annual Meeting of Orthopaedic Research Society (ORS), 44, PS1-054, 2019年02月
英語

歩行動画によるロコモ評価システムの開発
角家 健, 山本 強, 宝満 健太郎, 岩崎 倫政, 医科学応用研究財団研究報告, 38, 58, 60, 2019年
鈴木謙三記念医科学応用研究財団, 日本語

足部ウェアラブルセンサシステムで算出される時空間歩行パラメータの妥当性検証
宝満健太郎, 角家健, 岩崎倫政, 山本敬三, 北海道整形災害外科学会, 136th, 136th suppl, 90, 90, 2019年
北海道整形災害外科学会, 日本語

ウェアラブルシステムを使用した慢性期片麻痺患者の歩行解析
斉藤貴志, 佐伯拓馬, 五十嵐大貴, 宝満健太郎, 角家健, 岩崎倫政, 石田直樹, 北海道整形災害外科学会, 136th, 136th suppl, 91, 91, 2019年
北海道整形災害外科学会, 日本語

客観的に歩行パラメーターを測定する足部ウェアラブルセンサの有効性
宝満健太郎, 角家健, 山本敬三, 岩崎倫政, 日本整形外科学会雑誌, 92, 8, S2048, S2048, 2018年08月30日
(公社)日本整形外科学会, 日本語

北海道における整形外科基礎研究 基礎研究体制と概要 北海道大学整形外科　　　　　　　　　　　　　　　
角家 健, 近藤 英司, 高畑 雅彦, 須藤 英毅, 古川 潤一, 小野寺 智洋, アラー・テルカウイ, 岩崎 倫政, 北海道整形災害外科学会雑誌, 59, 2, 197, 204, 2018年03月
北海道整形災害外科学会, 日本語

BDNF Gene Delivery for Alzheimer's Disease
Mark H. Tuszynski, Krystof Bankiewicz, John Bringas, Imre Kovacs, Alan Nagahara, Jacob Koffler, Ken Kadoya, ANNALS OF NEUROLOGY, 82, S145, S145, 2017年10月
WILEY, 英語, 研究発表ペーパー・要旨（国際会議）

学術奨励賞・受賞記念論文 神経前駆細胞移植による脊髄損傷後の皮質脊髄路の再生
角家 健, Tuszynski Mark, 岩崎 倫政, 北海道整形災害外科学会雑誌 : 北海道整形災害外科学会機関誌, 59, 1, 1, 5, 2017年08月
北海道整形災害外科学会, 日本語

超高分子ポリエチレン摩耗粉によるヒトマクロファージの遺伝子発現変化は関節リウマチと類似する　　　　　　　　　　　　　　　
Terkawi Alaa, 濱崎 雅成, 高橋 大介, 角家 健, 浅野 毅, 入江 徹, 小野寺 智洋, 高畑 雅彦, 岩崎 倫政, 日本整形外科学会雑誌, 91, 8, S1722, S1722, 2017年08月
(公社)日本整形外科学会, 日本語

Progress and Setbacks in the Study of CNS Axonal Plasticity and Regeneration
Mark H. Tuszynski, Ken Kadoya, Paul Lu, Armin Blesch, Ephron Rosenzweig, John Brock, Karin Loew, FASEB JOURNAL, 24, 2010年04月
FEDERATION AMER SOC EXP BIOL, 英語, 研究発表ペーパー・要旨（国際会議）

脊髄損傷におけるT細胞活性化の役割-CTLA 4-Igによる補助シグナルブロック
永野裕介, 角家健, 眞島任史, 岩崎倫政, 本宮真, 三浪明男, 今重之, 上出利光, 移植, 41, 2, 2006年

脊髄損傷におけるT細胞活性化の役割-CTLA4-Igによる補助シグナルブロック-
永野裕介, 角家健, 本宮真, 三浪明男, 今重之, 上出利光, 日本整形外科学会雑誌, 79, 8, 2005年

転移性脊椎腫瘍に対する前方/前後合併進入法による椎体切除/脊椎全摘術の長期成績
武田 直樹, 小谷 善久, 角家 健, 伊東 学, 白土 修, 三浪 明男, 鐙 邦芳, 種市 洋, 金田 清志, 日本整形外科學會雜誌 = The Journal of the Japanese Orthopaedic Association, 78, 10, 711, 716, 2004年10月25日
日本整形外科学会, 日本語

外傷性腕神経損傷後に発生した巨大偽性髄膜りゅうの一例
久田幸由, 小谷善久, 鐙邦芳, 伊東学, 角家健, 白土修, 三浪明男, 寺江聡, 北海道整形災害外科学会雑誌, 46, 1, 26, 2004年09月10日
日本語

透析脊椎症の病態と手術治療
伊東 学, 鐙 邦芳, 小谷 善久, 武田 直樹, 竹林 武宏, 白土 修, 角家 健, 室田 栄宏, 三浪 明男, 日本脊椎脊髄病学会雑誌 = The journal of the Japan Spine Research Society, 15, 1, 96, 96, 2004年05月20日
日本語

側弯症後方矯正手術における椎弓根スクリュー刺入の精度評価 : 従来法とナビゲーション使用例の比較
小谷 善久, 鐙 邦芳, 伊東 学, 角家 健, 室田 栄宏, 三浪 明男, 日本脊椎脊髄病学会雑誌 = The journal of the Japan Spine Research Society, 15, 1, 251, 251, 2004年05月20日
日本語

環軸椎回旋位固定難治例の病態と治療
角家 健, 伊東 学, 鐙 邦芳, 小谷 善久, 室田 栄宏, 三浪 明男, 日本脊椎脊髄病学会雑誌 = The journal of the Japan Spine Research Society, 15, 1, 300, 300, 2004年05月20日
日本語

Two-year observation of artificial intervertebral disc replacement: results after supplemental ultra-high strength bioresorbable spinal stabilization.
Kotani Yoshihisa, Abumi Kuniyoshi, Shikinami Yasuo, Takahata Masahiko, Kadoya Ken, Kadosawa Tsuyoshi, Minami Akio, Kaneda Kiyoshi, Journal of Neurosurgery : Spine, 100, 4, 337, 342, 2004年04月
OBJECT: This 2-year experimental study was conducted to investigate the efficacy of a bioactive three-dimensional (3D) fabric disc for lumbar intervertebral disc replacement. The authors used a bioresorbable spinal fixation rod consisting of a forged composite of particulate unsintered hydroxyapatite/poly-L-lactide acid (HA/PLLA) for stability augmentation. The biomechanical and histological alterations as well as possible device-related loosening were examined at 2 years postoperatively. METHODS: Two lumbar intervertebral discs (L2-3 and L4-5) were replaced with the 3D fabric discs, which were augmented by two titanium screws and a spanning bioresorbable rod (HA/PLLA). The segmental biomechanics and interface bone ingrowth were investigated at 6, 15, and 24 months postoperatively, and results were compared with the other two surgical groups (3D fabric disc alone; 3D fabric disc with additional anterior instrumentation stabilization). The 3D fabric disc and HA/PLLA-spinal segments demonstrated segmental mobility at 15 and 24 months; however, the range of motion (ROM) in flexion-extension decreased to 49 and 40%, respectively, despite statistically equivalent preserved torsional ROM. Histologically there was excellent osseous fusion at the 3D fabric disc surface-vertebral body interface. At 2 years posttreatment, no adverse tissue reaction nor aseptic loosening of the device was observed. CONCLUSIONS: Intervertebral disc replacement with the 3D fabric disc was viable and when used in conjunction with the bioresorbable HA/PLLA spinal augmentation. Further refinements of device design to create a stand-alone type are necessary to obviate the need for additional spinal stabilization., American Association of Neurological Surgeons, 英語

脊髄損傷治療に対する免疫学的アプローチ
角家健, 三浪明男, 永野裕介, 今重之, 上出利光, 日本整形外科学会雑誌, 78, 8, 2004年

化膿性脊椎炎に対する椎間孔鏡視下手術の有用性
伊東 学, 鐙 邦芳, 白土 修, 小谷 善久, 角家 健, 三浪 明男, 吉本 尚, 日本脊椎脊髄病学会雑誌 = The journal of the Japan Spine Research Society, 14, 1, 156, 156, 2003年02月20日
日本語

頚椎々弓切除後々弯変形に対する椎弓根スクリューを用いた脊柱再建術
角家 健, 鐙 邦芳, 小谷 善久, 伊東 学, 白土 修, 三浪 明男, 日本脊椎脊髄病学会雑誌 = The journal of the Japan Spine Research Society, 14, 1, 105, 105, 2003年02月20日
日本語

頚椎外科におけるコンピューター支援手術の有用性
小谷 善久, 鐙 邦芳, 伊東 学, 角家 健, 三浪 明男, 日本脊椎脊髄病学会雑誌 = The journal of the Japan Spine Research Society, 14, 1, 10, 10, 2003年02月20日
日本語

環状骨端(Ring apophysis)の離解を伴う腰椎椎間板ヘルニアの手術治療 : 離解骨端の切除は、常に必須か?
白土 修, 角家 健, 伊東 学, 小谷 善久, 鐙 邦芳, 三浪 明男, 日本脊椎脊髄病学会雑誌 = The journal of the Japan Spine Research Society, 14, 1, 47, 47, 2003年02月20日
日本語

頚椎再建手術における椎弓根スクリュー固定の合併症と対策
鐙 邦芳, 伊東 学, 小谷 善久, 角家 健, 藤谷 正紀, 日本脊椎脊髄病学会雑誌 = The journal of the Japan Spine Research Society, 14, 1, 307, 307, 2003年02月20日
日本語

生体内吸収性内固定材料を応用した人工椎間板置換術 : 術後2年の検討から観た本法の将来戦略
小谷 善久, 鐙 邦芳, 高畑 雅彦, 高田 宇重, 角家 健, 島本 則道, 松本 聡子, 海老原 響, 伊東 学, 廉澤 剛, 敷波 保夫, 金田 清志, 三浪 明男, 日本脊椎脊髄病学会雑誌 = The journal of the Japan Spine Research Society, 13, 1, 7, 7, 2002年04月26日
日本語

高強度水酸アパタイト/ポリ-L-乳酸複合体による脊椎吸収性内固定
角家 健, 小谷 善久, 鐙 邦芳, 高田 宇重, 島本 則道, 廉沢 剛, 藤永 徹, 金田 清志, 三浪 明男, 日本脊椎脊髄病学会雑誌 = The journal of the Japan Spine Research Society, 12, 1, 288, 288, 2001年04月27日
日本語

骨粗鬆症性椎体圧潰発生のリスクファクター解析
種市 洋, 金田 清志, 小熊 忠教, 古梶 正洋, 角家 健, 須藤 英毅, 白土 修, 日本脊椎脊髄病学会雑誌 = The journal of the Japan Spine Research Society, 12, 1, 215, 215, 2001年04月27日
日本語

側弯症前方インストルメンテーションの生体力学的評価 : 骨・スクリュー界面の疲労解析
島本 則道, 小谷 善久, 庄野 泰弘, 角家 健, 鐙 邦芳, 金田 清志, 日本臨床バイオメカニクス学会誌 = Proceedings of ... Annual Meeting of Japanese Society for Clinical Biomechanics and Related Research, 21, 27, 32, 2000年10月01日
日本語

羊人工椎間板の粘弾性および疲労特性
角家 健, 小谷 善久, 鐙 邦芳, 金田 清志, 敷波 保夫, 日本臨床バイオメカニクス学会誌 = Proceedings of ... Annual Meeting of Japanese Society for Clinical Biomechanics and Related Research, 21, 49, 52, 2000年10月01日
日本語

人工椎間板と椎体の界面強度に関する生体力学的検討
高畑 雅彦, 小谷 善久, 角家 健, 高田 宇重, 島本 則道, 松本 聡子, 鐙 邦芳, 敷波 保夫, 廉澤 剛, 藤永 徹, 金田 清志, 日本整形外科學會雜誌, 74, 8, S1530, 2000年08月25日
日本語

人工椎間板全置換モデルにおける人工椎間板-椎体界面の組織形態計測学的検討
松本 聡子, 小谷 善久, 高田 宇重, 角家 健, 島本 則道, 高畑 雅彦, 敷波 保夫, 廉澤 剛, 藤永 徹, 鐙 邦芳, 金田 清志, 日本整形外科學會雜誌, 74, 8, S1531, 2000年08月25日
日本語

高強度水酸アパタイト/ポリ-L-乳酸複合体による脊椎吸収性内固定
角家 健, 小谷 善久, 鐙 邦芳, 高田 宇重, 島本 則道, 廉澤 剛, 藤永 徹, 敷波 保夫, 金田 清志, 日本整形外科學會雜誌, 74, 8, S1651, 2000年08月25日
日本語

多孔処理A-W G・C人工椎体による椎体置換に関する組織学的研究(第2報)
高田 宇重, 金田 清志, 小谷 善久, 鐙 邦芳, 島本 則道, 角家 健, 松本 聡子, 海老原 響, 森平 泰, 高畑 雅彦, 廉澤 剛, 藤永 徹, 下村 真司, 小松谷 俊介, 日本整形外科學會雜誌, 74, 8, S1818, 2000年08月25日
日本語

全置換型人工椎間板の開発と臨床応用への課題
小谷 善久, 金田 清志, 鐙 邦芳, 高田 宇重, 角家 健, 島本 則道, 松本 聡子, 高畑 雅彦, 廉澤 剛, 藤永 徹, 敷波 保夫, 日本整形外科學會雜誌, 74, 8, S1335, 2000年08月25日
日本語

多孔処理A-W G・C人工椎体による椎体置換に関する組織学的研究
高田 宇童, 小谷 善久, 鐙 邦芳, 島本 則道, 角家 健, 松本 聡子, 海老原 響, 金田 清志, 廉澤 剛, 下村 真司, 小松谷 俊介, 日本脊椎外科学会雑誌 = The journal of the Japan Spine Research Society, 11, 1, 82, 82, 2000年04月28日
日本語

生体内吸収性内固定材料を応用した人工椎間板全置換術
小谷 善久, 金田 清志, 鐙 邦芳, 高田 宇童, 敷波 保夫, 角家 健, 島本 則道, 松本 聡子, 廉澤 剛, 日本脊椎外科学会雑誌 = The journal of the Japan Spine Research Society, 11, 1, 120, 120, 2000年04月28日
日本語

生体内吸収性内固定材料を応用した人工椎間板全置換術
小谷 善久, 金田 清志, 鐙 邦芳, 高田 宇重, 角家 健, 島本 則道, 松本 聡子, 敷波 保夫, 廉澤 剛, 日本整形外科學會雜誌, 74, 2, S138, 2000年02月25日
日本語

多軸三次元立体織物による人工椎間板全置換術の生体力学的・組織学的検討(第一報)
小谷 善久, 金田 清志, 鐙 邦芳, 高田 宇重, 角家 健, 島本 則道, 諌山 治彦, 古梶 正洋, 廉澤 剛, 敷波 保夫, 日本臨床バイオメカニクス学会誌 = Proceedings of ... Annual Meeting of Japanese Society for Clinical Biomechanics and Related Research, 20, 13, 18, 1999年10月01日
日本語

三次元立体織物を使用した羊人工椎間板の生体力学的特性とその生体内変化
角家 健, 小谷 善久, 鐙 邦芳, 高田 宇重, 島本 則道, 諌山 治彦, 金田 清志, 廉澤 剛, 敷波 保夫, 日本臨床バイオメカニクス学会誌 = Proceedings of ... Annual Meeting of Japanese Society for Clinical Biomechanics and Related Research, 20, 1, 6, 1999年10月01日
日本語

人工椎間板の開発に関する生体力学的・組織学的研究(第2報)
小谷 善久, 金田 清志, 鐙 邦芳, 高田 宇重, 角家 健, 島本 則道, 海老原 響, 松本 聡子, 敷波 保夫, 廉澤 剛, 日本整形外科學會雜誌 = The Journal of the Japanese Orthopaedic Association, 73, 8, S1934, 1999年08月25日
日本語

三次元立体織物を使用した羊人工椎間板の粘弾性および疲労特性
角家 健, 小谷 善久, 鐙 邦芳, 敷波 保夫, 金田 清志, 日本脊椎外科学会雑誌 = The journal of the Japan Spine Research Society, 10, 1, 173, 173, 1999年04月26日
日本語

羊人工椎間板の引張・圧縮、捻り特性とその生体内変化
角家 健, 小谷 善久, 鐙 邦芳, 高田 宇重, 島本 則道, 諌山 治彦, 廉澤 剛, 敷波 保夫, 金田 清志, 日本脊椎外科学会雑誌 = The journal of the Japan Spine Research Society, 10, 1, 172, 172, 1999年04月26日
日本語

全置換型人工椎間板の開発と臨床応用の展望
小谷 善久, 金田 清志, 鐙 邦芳, 高田 宇重, 角家 健, 島本 則道, 敷波 保夫, 廉澤 剛, 日本脊椎外科学会雑誌 = The journal of the Japan Spine Research Society, 10, 1, 104, 104, 1999年04月26日
日本語

全置換型人工椎間板の開発と臨床応用の展望
小谷 善久, 金田 清志, 鐙 邦芳, 高田 宇重, 敷波 保夫, 角家 健, 島本 則道, 廉澤 剛, 日本整形外科學會雜誌 = The Journal of the Japanese Orthopaedic Association, 73, 2, S152, 1999年02月25日
日本語

Surgical treatment of avulsion fracture of the tibial attachment of the posterior cruciate ligament - First report: Posterior instability of the knee
E. Kondo, M. Inoue, M. Saita, T. Ohya, N. Iwasaki, H. Watanabe, K. Kadoya, N. Shimamoto, Hokkaido Journal of Orthopaedics and Traumatology, 41, 25, 29, 1998年12月01日
Nine patients with avulsion fractures of the tibial attachment of the posterior cruciate ligament (PCL)were treated by open reduction and internal fixation in the period from 1994 to 1997. The age of the patients averaged 50 years. Follow-up periods ranged from five months to 36 months (average: 16months). The patients had large bony fragment displaced by two mm or more. The avulsion fragment was reduced to the anatomical position and fixed with screws through the transpopliteal approach. At the time of final examination, roentgenograms showed that all fragments were healed in the anatomical position. The Lysholm knee scoring scale averaged 95±5 (Mean±S.D.) points. The average range of knee motion was 145±5 (Mean±S.D.) degrees postoperatively. Five of the nine patients showed the residual posterior sag sign and the positive posterior drawer test. Quantitative evaluation using a Knee Laxity Tester (Stryker Co. USA.) demonstrated that five patients had anterior-posterior total knee laxity more than three mm, compared with the normal knee. This study suggested that midsubstance failure of PCL may be combined with avulsion fracture of the tibial attachment of the PCL.

後十字靱帯脛骨付着部裂離骨折の手術治療(第一報) 特に後方動揺性について　　　　　　　　　　　　　　　
近藤 英司, 井上 雅之, 斉田 通則, 大矢 卓, 岩崎 倫政, 渡辺 裕樹, 角家 健, 島本 則道, 北海道整形災害外科学会雑誌, 41, 1, 25, 29, 1998年11月
対象は過去3年間に手術治療を要した9人9膝で,年齢は平均50歳,経過観察期間は平均16ヵ月であった.手術適応は裂離骨片の大きさが1cm以上で,後十字靱帯脛骨付着部より2mm以上転位しているものとした.手術は膝窩部を展開し裂離骨片を整復後,螺子固定を行った.術後,X線学的には全例整復位での骨癒合が得られていた.Lysholm knee scoring scaleは平均95点で,関節可動域は屈曲平均145度であった.sagging,後方引き出し試験が陽性であるものは9膝中5膝.Knee Laxity Tester(Stryker Co.USA)でのanteriorposterior total knee laxityは対健側差+2.7±1.6(平均±標準偏差)mmであり,5膝に3〜5.7mmの対健側差を認めた, 北海道整形災害外科学会, 日本語

羊人工椎間板の生体力学的特性とその生体内変化
角家 健, 金田 清志, 小谷 善久, 敷波 保夫, 鐙 邦芳, 高田 宇重, 島本 則道, 諌山 治彦, 廉澤 剛, 日本整形外科學會雜誌 = The Journal of the Japanese Orthopaedic Association, 72, 8, S1418, 1998年08月25日
日本語

人工椎間板の開発に関する生体力学的・組織学的研究(第1報)
小谷 善久, 金田 清志, 敷波 保夫, 鐙 邦芳, 高田 宇重, 角家 健, 島本 則道, 諌山 治彦, 廉澤 剛, 日本整形外科學會雜誌 = The Journal of the Japanese Orthopaedic Association, 72, 8, S1416, 1998年08月25日
日本語

移植組織制御による新規脊髄再生方法の開発
科学研究費助成事業 基盤研究(B)
2020年04月01日 - 2023年03月31日
角家 健
神経前駆細胞移植によって、脊髄損傷部を新しい神経組織で充たすことが可能になったが、正常組織と異なり、移植組織内の神経細胞の位置は全くの無秩序である。神経前駆細胞移植による機能再生効果を向上させるためには、秩序だった神経細胞の配置が重要であると予想されるが、未だ、移植神経細胞の位置を制御する方法は開発されていない。発生期では、神経前駆細胞がモルフォゲンの濃度勾配を位置情報として利用することで、脊髄組織の構成にパターンを形成する。そこで、本研究の目的は、脊髄損傷部に移植された神経前駆細胞はモルフォゲンの濃度勾配を位置情報として利用できるという仮説を検討することである。これまでに、マウスの５種類のモルフォゲン（BMP4、Wnt1、Sonic Hedge Hog、Netrin1、Draxin)のクローニングを完了し、第３世代のレンチウイルスによる、線維芽細胞への遺伝子導入システムを確立、各モルフォゲンとコントロールの計６種類のレンチウイルスを作成し、FACSを使用して、５種類のモルフォゲンを分泌する同系マウス由来の線維芽細胞の作成を完了した。また、これらの線維芽細胞の脊髄への移植方法と、胚性脊髄由来の神経前駆細胞を損傷部に移植し、新規神経組織の作成方法も確立した。最後に、免疫染色によって、移植神経細胞のパターン形成評価方法も確立した。
日本学術振興会, 基盤研究(B), 北海道大学, 20H03558

VCP化合物の最適化による新規神経保護薬の開発
科学研究費助成事業 基盤研究(C)
2020年04月01日 - 2023年03月31日
船木 智, 中川 慎介, 角家 健, 周東 智
脊髄損傷に対する有効な治療法はいまだ確立されておらず、その治療法の確立が求められている。これまでの研究から、一次損傷に引き続いておこる、血液脳脊髄関門の破綻を防ぐことで、二次損傷を軽減できる可能性が示されているが、その具体的な方法はいまだ確立されてない。本研究では、約2400の北海道大学独自の化合物をスクリーニングした結果、類似の化合物の類縁体１４剤が培養ヒト脳血管内皮細胞に対する細胞保護作用を持つことを見出した。そこで、本研究の目的は、これらの化合物の応用により、脳脊髄血管内皮細胞保護作用を介して、血液脳脊髄関門の破綻を防ぎ、脊髄損傷後の二次損傷を軽減することで、最終的に神経保護作用を発揮する新規神経保護薬を開発することである。本年度は、代表的なVCP化合物を大量に作成し、正常マウス、および脊髄損傷マウスに腹腔内投与して、経時的血液濃度を測定した。その結果、培養脳血管内皮細胞に有効であった濃度と同様の血中濃度が腹腔内投与でも得られること、VCP化合物の投与によって明らかな副作用を生じないこと、VCP化合物の腹腔内投与によってマウス脊髄損傷後のIgG漏出面積を抑制することを確認した。このことは、VCP化合物が、腹腔内投与で動物実験に使用可能なほど安全で、脊髄損傷後の血液脊髄関門機能の破綻を抑制することを示している。現在、VCP化合物による脊髄損傷後の組織保護効果、機能保護効果を検討中である。
日本学術振興会, 基盤研究(C), 北海道大学, 20K09449

ウエアラブル端末を用いた高齢者の認知機能に影響する歩行パラメータと修飾要因の検討
科学研究費助成事業 挑戦的研究(開拓)
2020年04月01日 - 2022年03月31日
玉腰 暁子, 角家 健, 鵜川 重和, 森 太郎
自立した生活を営むためには、自身の力で思うところに動けること、すなわち歩けることが基本となる。本研究は、北海道内6町在住の介護認定を受けていない70‐79歳を対象に、非侵襲、簡便かつ同時に複数のパラメータを測定できるウエアラブル端末を用いて歩行パラメータの把握を行い、その後の認知機能低下との関連を検討すること、さらに、その関連を修飾する身体機能、冬季及び夏季の身体活動を含む生活習慣、屋内環境、近隣環境を探索し、認知機能低下に資する介入可能要因を明らかにすることを目的としている。
2018年度に調査を行った歩行パラメータと認知機能との関連を利用可能であった236名を対象に横断的に解析した。得られたパラメータのうち意義等が重複するものを除いた20のパラメータを統計学的に総合したところ、4つの歩行因子が抽出された（一般的なサイクル、初期接触、推進力、ミッド・スイング）。これらのうち、いくつかの要因で調整した後もMoCA-Jで測定した認知機能との関連を示したのは、一般的なサイクルであった。また、認知機能のドメインで見ると、一般的なサイクルは実行機能と記憶に、初期接触は実行機能と関連していた。
一方、今年度は2018年度の調査参加者を対象に、変化を把握するための調査を実施する予定であったが、新型コロナウイルス感染症拡大防止を考え、調査を中止せざるを得なかった。来年度に向けて、改めて対象地域担当者との調整を行い、2018年度と同時期の調査を行う予定である。
日本学術振興会, 挑戦的研究(開拓), 北海道大学, 20K20395

末梢神経の軸索再生を支える細胞機構と接着因子の解明　　　　　　　　　　　　　　　
革新的先端研究開発支援事業プライム
2018年10月 - 2022年03月
国立研究開発法人日本医療研究開発機構, プライム, 研究代表者, 20gm6210004h0003

脊髄損傷に対する新規神経保護薬の開発
科学研究費助成事業 基盤研究(C)
2017年04月01日 - 2020年03月31日
浅野 毅, 中川 慎介, 角家 健
血液脳脊髄関門保護効果を有する薬剤同定のハイスループットスクリーニング（HTS）方法を確立した。次に、既存薬のスクリーニングによって、候補薬剤を同定し、in vitro血液脳脊髄関門モデル、マウス脊髄損傷モデルによって、候補薬剤が血液脳脊髄関門保護効果を持つことを確認した。また、候補薬剤の１つであるBerberineを脊髄損傷マウスに投与することで、歩行機能が向上し、損傷脊髄の損傷範囲が減少することが明らかになった。これら一連の結果は、今回開発したHTS方法が血液脳脊髄関門機能保護効果を持つ薬剤の絞り込みに有用であり、同定された薬剤が脊髄損傷に対する神経保護効果を持つことを示している。
日本学術振興会, 基盤研究(C), 北海道大学, 17K10913

軸索再生に至適なシュワン細胞の同定
科学研究費助成事業 基盤研究(C)
2017年04月01日 - 2020年03月31日
河村 太介, 角家 健
移植細胞の末梢神経軸索再生効果を定量する独自の動物モデルを開発し、シュワン細胞、線維芽細胞、骨髄間質性細胞を比較した結果、シュワン細胞のみが軸索再生効果を持ち、移植細胞の種類に関わらず、軸索再生量はシュワン細胞量に相関していた。引き続いて、４種類のシュワン細胞（前駆、未熟、修復、非修復）を比較した結果、修復細胞が最も軸索再生効果に優れ、前駆細胞と未熟細胞には軸索再生効果がないことを明らかにした。培養神経細胞の神経突起伸張効果、神経栄養因子分泌量、トランスクリプトームもこの結果を支持していた。これらの知見は、末梢神経の軸索再生の機序解明、再生促進方法の開発に貢献する。
日本学術振興会, 基盤研究(C), 北海道大学, 17K10914

神経幹細胞移植による慢性期脊髄損傷での神経回路再形成
科学研究費助成事業 基盤研究(C)
2017年04月01日 - 2020年03月31日
角家 健
神経幹細胞をラット慢性期脊髄損傷部に移植した結果、亜急性期移植と同等の移植細胞の生着を認め、損傷部が新しい神経組織で再構成された。また、移植神経細胞は亜急性期移植と同等の旺盛な軸索伸展を示し、宿主神経細胞と神経回路を形成した。慢性的に損傷されていた皮質脊髄路軸索も移植細胞内へと再生し、神経回路を形成したが、その程度は亜急性期移植に劣っていた。神経幹細胞の慢性期脊髄損傷部への移植の結果、損傷部の瘢痕組織の低形成化を認めた。慢性期であっても、神経幹細胞移植は脊髄損傷部に神経回路を再形成することができる。
日本学術振興会, 基盤研究(C), 北海道大学, 17K10915

複合細胞移植による新規末梢神経再生方法の開発
科学研究費助成事業 基盤研究(C)
2017年04月01日 - 2020年03月31日
永野 裕介, テルカウィ アラー, 角家 健
本研究の目的は、マクロファージの亜型による軸索再生効果の違いを明らかにし、末梢神経の軸索再生に有効な複合細胞治療方法の基礎を確立することである。ラット坐骨神経の圧挫モデルを使用して、軸索再生とマクロファージの時空間的な変化を検討したところ、M2細胞は軸索再生部位と比較的一致していた。M2マクロファージ移植は軸索再生効果を認めたが、M１マクロファージでは認めなかった。その効果は、同系移植でのみ認め、同種移植では認めなかった。また、M2マクロファージ移植は、運動機能、神経生理機能の回復を部分的に促進することも確認した。
日本学術振興会, 基盤研究(C), 北海道大学, 17K11527

中枢神経の再生関連遺伝子の同定:皮質脊髄路の軸索再生
科学研究費助成事業 研究活動スタート支援
2015年08月28日 - 2017年03月31日
角家 健, 遠藤 健
末梢神経では、いくつかの再生関連遺伝子が同定されているが、中枢神経で同様の報告はない。本研究は、転写因子cJunが末梢神経と同様に、中枢神経でも再生関連遺伝子であるか検討した。中枢神経である皮質脊髄路軸索が移植細胞内へと再生するモデルを使用し、cJunの発現を操作したが、軸索再生の程度は変化しなかった。このことは、cJunは皮質脊髄路の再生関連遺伝子ではなく、また、中枢神経の再生メカニズムは、末梢神経と異なることを示している。
日本学術振興会, 研究活動スタート支援, 北海道大学, 15H05989

脊髄誘発電位測定用電極および脊髄誘発電位測定装置
特許権, 及川 陽一, 古川 博之, 角家 健, 永野 裕介, 富士通株式会社, 国立大学法人 北海道大学
特願2004-381997, 2004年12月28日
特開2006-187342, 2006年07月20日
200903075038255563

神経突起伸長促進剤及び神経再生誘導用医薬組成物　　　　　　　　　　　　　　　
特許権, 角家健, 鈴木智亮
特願2021-160064

末梢神経損傷の治療のための医薬組成物　　　　　　　　　　　　　　　
特許権, 角家健, 山本康弘
特願2021-126207

ＧＦＲα１を含む神経突起伸長促進剤及び神経再生誘導用医療材料　　　　　　　　　　　　　　　
特許権, 角家健, 鈴木智亮, 遠藤健
特願2020- 218091

血液脳脊髄関門保護剤　　　　　　　　　　　　　　　
特許権, 角家健、鈴木裕貴、五月女慧人、前仲勝実、乙黒聡子
特願2020-109190

破骨細胞分化抑制剤　　　　　　　　　　　　　　　
特許権, テルカウイ モハマド, アラー, ハッサン シエーク, 角家健, 高橋大介, 岩崎倫政
特願1. 2018-148040