Researcher basic information

• Hokkaido University

• 理学博士, Keimyung University, South Korea, Aug. 2007

• https://researchmap.jp/7000014933?lang=en

• https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201601018771698050
• https://www.den.hokudai.ac.jp/biochem/

• 70711274

• 201601018771698050

• Brain
• Microglia
• Informatics
• osteoblast
• Osteoclast
• Bone metabolism

• Life Science, Molecular biology, Bone Metabolism, Osteoclast, Osteoblast
• Life Science, Cell biology

• Bachelor's degree program, School of Dental Medicine
• Doctoral (PhD) degree program, Graduate school of Dental Medicine

Research activity information

• 2018, The 3rd Meeting of Japanese Osteoimmunology, Excellent Academic Award
  Lee Ji-Won
• 2017, The 37th Annual Meeting of Japanese Society for Bone Morphometry, Best Academic Award
  Lee Ji-Won
• 2017, Joint Meeting of the Australian and New Zealand Bone and Mineral Society and The International Federation of Musculoskeletal Research Societies, Travel Award
  Lee Ji-Won
• 2016, 43rd Annual European Calcified Tissue Society Congress, Best Poster Presentation Prize
  Lee Ji-Won
• 2013, Shimanami Bone and Joint Forum, Young Investigator Award
  Lee Ji-Won
• 2003, The Korean Journal of Food and Science Technology, Graduate Student Presentation Awards
  Lee Ji-Won

• Lithium and the Brain-Bone Axis: A Bridge between Osteoporosis and Alzheimer's Disease.
  Ji-Won Lee; Tomoka Hasegawa; Aoi Ikedo; Kaito Mizuno; Norio Amizuka; Sek Won Kong
  Current osteoporosis reports, 24, 1, 7, 7, 10 Feb. 2026, [International Magazine]
  English, Scientific journal, PURPOSE OF REVIEW: We evaluate the converging evidence positioning lithium as a systemic modulator of bone and brain health through shared molecular pathways. This review examines the molecular basis, preclinical data, and clinical observations suggesting that lithium-long established as first-line therapy for bipolar disorder-may simultaneously protect against osteoporosis and neurodegeneration as two clinical conditions increasingly recognized to share biological substrates. RECENT FINDINGS: Lithium inhibits glycogen synthase kinase-3β (GSK-3β), stabilizes β-catenin, and activates Wnt signaling in neurons and osteoblasts, while also modulating calcium-inositol homeostasis and suppressing NF-κB-mediated inflammation. Large observational studies report lower dementia incidence and reduced fracture risk in long-term lithium users, together with increases in bone mineral density. Declining brain lithium concentrations in patients with Alzheimer's disease raise the hypothesis that lithium may act as an essential micronutrient rather than solely a pharmacological agent. Bidirectional brain-bone crosstalk involving osteocalcin signaling and sclerostin transport across the blood-brain barrier provides a mechanistic basis for these pleiotropic effects. Lithium offers a unique paradigm for understanding and potentially treating age-related decline in multiple organ systems at subclinical dosage and concentration. However, observational study limitations, optimal dose uncertainties, and toxicity related to long-term usage concerns necessitate rigorous randomized controlled trials before broader clinical recommendations can be made. Future research should focus on optimizing formulation and patient selection to realize lithium's dual protective potential for bone and brain while minimizing risk.
• Neuropilin-2 functions as a coinhibitory receptor to regulate antigen-induced inflammation and allograft rejection.
  Johannes Wedel; Nora Kochupurakkal; Sek Won Kong; Sayantan Bose; Ji-Won Lee; Madeline Maslyar; Bayan Alsairafi; Kayla MacLeod; Kaifeng Liu; Hengcheng Zhang; Masaki Komatsu; Hironao Nakayama; Diane R Bielenberg; David M Briscoe
  The Journal of clinical investigation, 135, 13, 01 Jul. 2025, [International Magazine]
  English, Scientific journal, Coinhibitory receptors function as central modulators of the immune response to resolve T effector activation and/or to sustain immune homeostasis. Here, using humanized SCID mice, we found that neuropilin-2 (NRP2) is inducible on late effector and exhausted subsets of human CD4+ T cells and that it is coexpressed with established coinhibitory molecules including PD-1, CTLA4, TIGIT, LAG3, and TIM3. In murine models, we also found that NRP2 is expressed on effector memory CD4+ T cells with an exhausted phenotype and that it functions as a key coinhibitory molecule. Knockout (KO) of NRP2 resulted in hyperactive CD4+ T cell responses and enhanced inflammation in delayed-type hypersensitivity and transplantation models. After cardiac transplantation, allograft rejection and graft failure were accelerated in global as well as CD4+ T cell-specific KO recipients, and enhanced alloimmunity was dependent on NRP2 expression on CD4+ T effectors but not on CD4+Foxp3+ Tregs. Also, KO Tregs were found to be as efficient as WT cells in the suppression of effector responses in vitro and in vivo. These collective findings identify NRP2 as a potentially novel coinhibitory receptor and demonstrate that its expression on CD4+ T effector cells is of great functional importance in immunity.
• Selective Pyk2 inhibition enhances bone restoration through SCARA5-mediated bone marrow remodeling in ovariectomized mice.
  Yunqing Liu; Mai Nishiura; Mika Fujii; Sumiti Sandhu; Yasutaka Yawaka; Yutaka Yamazaki; Akira Hasebe; Tadahiro Iimura; Sek Won Kong; Ji-Won Lee
  Cell communication and signaling : CCS, 22, 1, 561, 561, 22 Nov. 2024, [Peer-reviewed], [Corresponding author], [International Magazine]
  English, Scientific journal, Understanding the intricate cellular interactions involved in bone restoration is crucial for developing effective strategies to promote bone healing and mitigate conditions such as osteoporosis and fractures. Here, we provide compelling evidence supporting the anabolic effects of a pharmacological Pyk2 inhibitor (Pyk2-Inh) in promoting bone restoration. In vitro, Pyk2 signaling inhibition markedly enhances alkaline phosphatase (ALP) activity, a hallmark of osteoblast differentiation, through activation of canonical Wnt/β-catenin signaling. Notably, analysis of human mesenchymal stem cells through RNA-seq revealed a novel candidate, SCARA5, identified through Pyk2-Inh treatment. We demonstrate that Scara5 plays a crucial role in suppressing the differentiation from stromal cells into adipocytes, and accelerates lineage commitment to osteoblasts, establishing Scara5 as a negative regulator of bone formation. Additionally, Pyk2 inhibition significantly impedes osteoclast differentiation and bone resorption. In a co-culture system comprising osteoblasts and osteoclasts, Pyk2-Inh effectively suppressed osteoclast differentiation, accompanied by a substantial increase in the transcriptional expression of Tnfrsf11b and Csf1 in osteoblasts, highlighting a dual regulatory role in osteoblast-osteoclast crosstalk. In an ovariectomized mouse model of osteoporosis, oral administration of Pyk2-Inh significantly increased bone mass by simultaneously reducing bone resorption, promoting bone formation and decreasing bone marrow fat. These results suggest Pyk2 as a potential therapeutic target for both adipogenesis and osteogenesis in bone marrow. Our findings underscore the importance of Pyk2 signaling inhibition as a key regulator of bone remodeling, offering promising prospects for the development of novel osteoporosis therapies.
• Enhanced phagocytosis associated with multinucleated microglia via Pyk2 inhibition in an acute β-amyloid infusion model.
  Ji-Won Lee; Kaito Mizuno; Haruhisa Watanabe; In-Hee Lee; Takuya Tsumita; Kyoko Hida; Yasutaka Yawaka; Yoshimasa Kitagawa; Akira Hasebe; Tadahiro Iimura; Sek Won Kong
  Journal of neuroinflammation, 21, 1, 196, 196, 06 Aug. 2024, [Peer-reviewed], [Lead author, Corresponding author], [International Magazine]
  English, Scientific journal, Multinucleated microglia have been observed in contexts associated with infection, inflammation, and aging. Though commonly linked to pathological conditions, the larger cell size of multinucleated microglia might enhance their phagocytic functions, potentially aiding in the clearance of brain debris and suggesting a reassessment of their pathological significance. To assess the phagocytic capacity of multinucleated microglia and its implications for brain debris clearance, we induced their formation by inhibiting Pyk2 activity using the pharmacological inhibitor PF-431396, which triggers cytokinesis regression. Multinucleated microglia demonstrate enhanced phagocytic function, as evidenced by their increased capacity to engulf β-amyloid (Aβ) oligomers. Concurrently, the phosphorylation of Pyk2, induced by Aβ peptide, was diminished upon treatment with a Pyk2 inhibitor (Pyk2-Inh, PF-431396). Furthermore, the increased expression of Lamp1, a lysosomal marker, with Pyk2-inh treatment, suggests an enhancement in proteolytic activity. In vivo, we generated an acute Alzheimer's disease (AD) model by infusing Aβ into the brains of Iba-1 EGFP transgenic (Tg) mice. The administration of the Pyk2-Inh led to an increased migration of microglia toward amyloid deposits in the brains of Iba-1 EGFP Tg mice, accompanied by morphological activation, suggesting a heightened affinity for Aβ. In human microglia, lipopolysaccharide (LPS)-induced inflammatory responses showed that inhibition of Pyk2 signaling significantly reduced the transcription and protein expression of pro-inflammatory markers. These results suggest that Pyk2 inhibition can modulate microglial functions, potentially reducing neuroinflammation and aiding in the clearance of neurodegenerative disease markers. This highlights Pyk2 as a promising target for therapeutic intervention in neurodegenerative diseases.
• 日本人腸内細菌叢の多様性解析 組成分析を用いた相対的アプローチ(Diversity of the Japanese Gut Microbiome Analysis: Relative Approach Using Compositional Analysis)
  板垣 竜樹; 中村 圭佑; 中野 晋太郎; 笠井 満知子; Lee Ji-Won; 長谷部 晃
  日本細菌学雑誌, 79, 2, 128, 128, 日本細菌学会, Jun. 2024
  English
• Viral uptake and pathophysiology of the lung endothelial cells in age-associated severe SARS-CoV-2 infection models.
  Takuya Tsumita; Ryo Takeda; Nako Maishi; Yasuhiro Hida; Michihito Sasaki; Yasuko Orba; Akihiko Sato; Shinsuke Toba; Wataru Ito; Takahito Teshirogi; Yuya Sakurai; Tomohiro Iba; Hisamichi Naito; Hitoshi Ando; Haruhisa Watanabe; Amane Mizuno; Toshiki Nakanishi; Aya Matsuda; Ren Zixiao; Ji-Won Lee; Tadahiro Iimura; Hirofumi Sawa; Kyoko Hida
  Aging cell, 23, 2, e14050, Wiley, Feb. 2024, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Abstract
  
  Thrombosis is the major cause of death in severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, and the pathology of vascular endothelial cells (ECs) has received much attention. Although there is evidence of the infection of ECs in human autopsy tissues, their detailed pathophysiology remains unclear due to the lack of animal model to study it. We used a mouse‐adapted SARS‐CoV‐2 virus strain in young and mid‐aged mice. Only mid‐aged mice developed fatal pneumonia with thrombosis. Pulmonary ECs were isolated from these infected mice and RNA‐Seq was performed. The pulmonary EC transcriptome revealed that significantly higher levels of viral genes were detected in ECs from mid‐aged mice with upregulation of viral response genes such as DDX58 and IRF7. In addition, the thrombogenesis‐related genes encoding PLAT, PF4, F3 PAI‐1, and P‐selectin were upregulated. In addition, the inflammation‐related molecules such as CXCL2 and CXCL10 were upregulated in the mid‐aged ECs upon viral infection. Our mouse model demonstrated that SARS‐CoV‐2 virus entry into aged vascular ECs upregulated thrombogenesis and inflammation‐related genes and led to fatal pneumonia with thrombosis. Current results of EC transcriptome showed that EC uptake virus and become thrombogenic by activating neutrophils and platelets in the aged mice, suggesting age‐associated EC response as a novel finding in human severe COVID‐19.
• Centrosome clustering control in osteoclasts through CCR5-mediated signaling
  Ji-Won Lee; In-Hee Lee; Haruhisa Watanabe; Yunqing Liu; Kazuaki Sawada; Masashi Maekawa; Shunsuke Uehara; Yasuhiro Kobayashi; Yuuki Imai; Sek Won Kong; Tadahiro Iimura
  Scientific Reports, 13, 1, Springer Science and Business Media LLC, 27 Nov. 2023, [Peer-reviewed], [Lead author, Corresponding author]
  Scientific journal, Abstract
  
  Osteoclasts uniquely resorb calcified bone matrices. To exert their function, mature osteoclasts maintain the cellular polarity and directional vesicle trafficking to and from the resorbing bone surface. However, the regulatory mechanisms and pathophysiological relevance of these processes remain largely unexplored. Bone histomorphometric analyses in Ccr5-deficient mice showed abnormalities in the morphology and functional phenotype of their osteoclasts, compared to wild type mice. We observed disorganized clustering of nuclei, as well as centrosomes that organize the microtubule network, which was concomitant with impaired cathepsin K secretion in cultured Ccr5-deficient osteoclasts. Intriguingly, forced expression of constitutively active Rho or Rac restored these cytoskeletal phenotypes with recovery of cathepsin K secretion. Furthermore, a gene-disease enrichment analysis identified that PLEKHM1, a responsible gene for osteopetrosis, which regulates lysosomal trafficking in osteoclasts, was regulated by CCR5. These experimental results highlighted that CCR5-mediated signaling served as an intracellular organizer for centrosome clustering in osteoclasts, which was involved in the pathophysiology of bone metabolism.
• AI駆動型形態計測を用いたイヌ皮質骨ハバース管リモデリングに対する骨形成促進薬テリパラチドの薬理作用
  星 麻里絵[沼端]; 高倉 綾; 中西 徳子[木村]; 李 智媛; 佐藤 嘉晃; 高尾 亮子; 飯村 忠浩
  日本骨形態計測学会雑誌, 33, 1, 172, 172, 日本骨形態計測学会, May 2023
  Japanese
• Association between an Increased Serum CCL5 Level and Pathophysiology of Degenerative Joint Disease in the Temporomandibular Joint in Females.
  Haruhisa Watanabe; Takashi Iori; Ji-Won Lee; Takashi S Kajii; Aya Takakura; Ryoko Takao-Kawabata; Yoshimasa Kitagawa; Yutaka Maruoka; Tadahiro Iimura
  International journal of molecular sciences, 24, 3, 01 Feb. 2023, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Degenerative joint disease of the temporomandibular joints (DJD-TMJ) clinically manifests with symptoms such as orofacial pain, joint sounds and limited jaw movements. Our research group previously reported the functional necessity of a chemokine-chemokine receptor axis of CCL5-CCR5 in osteoclasts. Accumulated studies reported that this axis was involved in the pathogenesis of bone and joint destructive diseases, suggesting CCL5 as a potent biomarker. This study investigated whether or not the serum level of CCL5 can be a biomarker of DJD-TMJ and concomitantly analyzed changes in the serum and urine levels of bone markers to see whether or not changes in the rate of bone metabolism were predisposing. We enrolled 17 female subjects with diagnosed DJD-TMJ and sexually and age-matched 17 controls. The serum CCL5 level in DJD-TMJ subjects was significantly higher than that in the control subjects. Multivariate analyses indicated an association between an augmented CCL5 level and the rate of bone metabolism, especially in relatively young DJD-TMJ subjects without other systemic symptoms. A principal component analysis of serum markers and our pharmacological experiment using a postmenopausal model of ovariectomized rats suggested that an augmented serum CCL5 level specifically reflected DJD-TMJ and that covert changes in the rate of bone metabolism predisposed individuals to DJD-TMJ.
• Expansion of the osteocytic lacunar-canalicular system involved in pharmacological action of PTH revealed by AI-driven fluorescence morphometry in female rabbits.
  Aya Takakura; Takanori Sato; Ji-Won Lee; Kyoko Hirano; Ryoko Takao-Kawabata; Toshinori Ishizuya; Tadahiro Iimura
  Scientific reports, 12, 1, 16799, 16799, 07 Oct. 2022, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Osteoporosis is an age-related disorder that is characterized by reduced bone mass. Its prevention and treatment are important healthcare issues for maintaining social activity in aged societies. Although bone fractures mostly occur at sites of weakened cortical bone, pathophysiological and pharmacological evaluations of bone mass have tended to be predominantly assessed in trabecular bone. To statistically characterize cortical bone remodeling, we originally established multimode fluorescence imaging and artificial intelligence (AI)-driven morphometric analyses in six-month-old female rabbits with well-defined cortical remodeling, similar to that in humans. We evaluated three distinct administration frequencies of teriparatide [TPTD; human parathyroid hormone, hPTH (1-34)]: once (1/w), twice (2/w), and seven times (7/w) a week, with the same total dose (140 μg/kg/week). Our analyses revealed significant expansions of the osteocytic lacunar-canalicular system and Haversian canals accompanied by the development of cortical porosity and endosteal naïve bone formation induced by a frequent administration regimen (7/w) of TPTD; however, once-weekly (1/w) and twice-weekly (2/w) administration of TPTD showed little effect. These findings demonstrate a clear contrast between the effects of frequent and infrequent administration of TPTD on cortical bone metabolism and suggest that osteocytic bone remodeling is involved in the pharmacological action of PTH.
• 最新の歯学 矯正治療時における骨メカノセンサーとしての骨細胞の役割
  中西 徳子[木村]; 星 麻里絵[沼端]; 佐藤 孝紀; 李 智媛; 佐藤 嘉晃; 飯村 忠浩
  北海道歯学雑誌, 43, 5, 8, 北海道歯学会, Sep. 2022, [Peer-reviewed]
  Japanese
• Evolution of multiple omics approaches to define pathophysiology of pediatric acute respiratory distress syndrome.
  Jane E Whitney; In-Hee Lee; Ji-Won Lee; Sek Won Kong
  eLife, 11, 01 Aug. 2022, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Pediatric acute respiratory distress syndrome (PARDS), though both common and deadly in critically ill children, lacks targeted therapies. The development of effective pharmacotherapies has been limited, in part, by lack of clarity about the pathobiology of pediatric ARDS. Epithelial lung injury, vascular endothelial activation, and systemic immune activation are putative drivers of this complex disease process. Prior studies have used either hypothesis-driven (e.g., candidate genes and proteins, in vitro investigations) or unbiased (e.g., genome-wide association, transcriptomic, metabolomic) approaches to predict clinical outcomes and to define subphenotypes. Advances in multiple omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, have permitted more comprehensive investigation of PARDS pathobiology. However, omics studies have been limited in children compared to adults, and analyses across multiple tissue types are lacking. Here, we synthesized existing literature on the molecular mechanism of PARDS, summarized our interrogation of publicly available genomic databases to determine the association of candidate genes with PARDS phenotypes across multiple tissues and cell types, and integrated recent studies that used single-cell RNA sequencing (scRNA-seq). We conclude that novel profiling methods such as scRNA-seq, which permits more comprehensive, unbiased evaluation of pathophysiological mechanisms across tissue and cell types, should be employed to investigate the molecular mechanisms of PRDS toward the goal of identifying targeted therapies.
• Histone H3K27 demethylase, Utx, regulates osteoblast-to-osteocyte differentiation.
  Yuhan Xia; Aoi Ikedo; Ji-Won Lee; Tadahiro Iimura; Kazuki Inoue; Yuuki Imai
  Biochemical and biophysical research communications, 590, 132, 138, 29 Jan. 2022, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Osteocytes are master regulators of skeletal homeostasis. However, little is known about the molecular mechanism of their differentiation. Epigenetic regulations, especially H3K27me3 modification, play critical roles in cell differentiation. Here, we found that H3K27me3 in the loci of osteocyte-expressing genes decreased during osteocyte differentiation and that H3K27me3 demethylase, Utx, was bound to the loci of those genes. To investigate the physiological functions of Utx in vivo, we generated late osteoblast-to-osteocyte specific Utx knockout mice using Dmp1-cre mice (UtxΔOcy/ΔOcy). Micro CT analyses showed that UtxΔOcy/ΔOcy displayed osteopenic phenotypes with lower bone volume and trabecular number, and greater trabecular separation. Bone histomorphometric analysis showed that bone mineralization and formation were significantly lower in UtxΔOcy/ΔOcy. Furthermore, Dmp1 expression and the number of osteocytes were significantly decreased in UtxΔOcy/ΔOcy. These results suggest that Utx in Dmp1-expressing osteoblast/osteocyte positively regulates osteoblast-to-osteocyte differentiation through H3K27me3 modifications in osteocyte genes. Our results provide new insight into the molecular mechanism of osteocyte differentiation.
• The Lipid-Binding Defective Dynamin 2 Mutant in Charcot-Marie-Tooth Disease Impairs Proper Actin Bundling and Actin Organization in Glomerular Podocytes.
  Eriko Hamasaki; Natsuki Wakita; Hiroki Yasuoka; Hikaru Nagaoka; Masayuki Morita; Eizo Takashima; Takayuki Uchihashi; Tetsuya Takeda; Tadashi Abe; Ji-Won Lee; Tadahiro Iimura; Moin A Saleem; Naohisa Ogo; Akira Asai; Akihiro Narita; Kohji Takei; Hiroshi Yamada
  Frontiers in cell and developmental biology, 10, 884509, 884509, 2022, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Dynamin is an endocytic protein that functions in vesicle formation by scission of invaginated membranes. Dynamin maintains the structure of foot processes in glomerular podocytes by directly and indirectly interacting with actin filaments. However, molecular mechanisms underlying dynamin-mediated actin regulation are largely unknown. Here, biochemical and cell biological experiments were conducted to uncover how dynamin modulates interactions between membranes and actin in human podocytes. Actin-bundling, membrane tubulating, and GTPase activities of dynamin were examined in vitro using recombinant dynamin 2-wild-type (WT) or dynamin 2-K562E, which is a mutant found in Charcot-Marie-Tooth patients. Dynamin 2-WT and dynamin 2-K562E led to the formation of prominent actin bundles with constant diameters. Whereas liposomes incubated with dynamin 2-WT resulted in tubule formation, dynamin 2-K562E reduced tubulation. Actin filaments and liposomes stimulated dynamin 2-WT GTPase activity by 6- and 20-fold, respectively. Actin-filaments, but not liposomes, stimulated dynamin 2-K562E GTPase activity by 4-fold. Self-assembly-dependent GTPase activity of dynamin 2-K562E was reduced to one-third compared to that of dynamin 2-WT. Incubation of liposomes and actin with dynamin 2-WT led to the formation of thick actin bundles, which often bound to liposomes. The interaction between lipid membranes and actin bundles by dynamin 2-K562E was lower than that by dynamin 2-WT. Dynamin 2-WT partially colocalized with stress fibers and actin bundles based on double immunofluorescence of human podocytes. Dynamin 2-K562E expression resulted in decreased stress fiber density and the formation of aberrant actin clusters. Dynamin 2-K562E colocalized with α-actinin-4 in aberrant actin clusters. Reformation of stress fibers after cytochalasin D-induced actin depolymerization and washout was less effective in dynamin 2-K562E-expressing cells than that in dynamin 2-WT. Bis-T-23, a dynamin self-assembly enhancer, was unable to rescue the decreased focal adhesion numbers and reduced stress fiber density induced by dynamin 2-K562E expression. These results suggest that the low affinity of the K562E mutant for lipid membranes, and atypical self-assembling properties, lead to actin disorganization in HPCs. Moreover, lipid-binding and self-assembly of dynamin 2 along actin filaments are required for podocyte morphology and functions. Finally, dynamin 2-mediated interactions between actin and membranes are critical for actin bundle formation in HPCs.
• A Quantitative Analysis of Bone Lamellarity and Bone Collagen Linearity Induced by Distinct Dosing and Frequencies of Teriparatide Administration in Ovariectomized Rats and Monkeys.
  Takanori Sato; Aya Takakura; Ji-Won Lee; Kazuaki Tokunaga; Haruka Matsumori; Ryoko Takao-Kawabata; Tadahiro Iimura
  Microscopy (Oxford, England), 08 Jun. 2021, [Peer-reviewed], [International Magazine]
  English, Scientific journal, The lamellar structure of bone, which endows biomechanical rigidity to support the host organism is observed in mammals, including humans. It is therefore essential to develop a quantitative analysis to evaluate the lamellarity of bone, which would especially useful for the pharmacological evaluation of anti-osteoporotic drugs. This study applied a current system for the semi-automatic recognition of fluorescence signals to the analysis of un-decalcified bone sections from rat and monkey specimens treated with teriparatide (TPTD). Our analyses on bone formation pattern and collagen topology indicated that TPTD augmented bone lamellarity and bone collagen linearity, which were possibly associated with the recovery of collagen crosslinking, thus endowing bone rigidity.
• Genetic variation analyses indicate conserved SARS-CoV-2-host interaction and varied genetic adaptation in immune response factors in modern human evolution.
  Ji-Won Lee; In-Hee Lee; Takanori Sato; Sek Won Kong; Tadahiro Iimura
  Development, growth & differentiation, 63, 3, 219, 227, Apr. 2021, [Peer-reviewed], [Lead author], [Domestic magazines]
  English, Scientific journal, Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a pandemic as of early 2020. Upon infection, SARS-CoV-2 attaches to its receptor, that is, angiotensin-converting enzyme 2 (ACE2), on the surface of host cells and is then internalized into host cells via enzymatic machineries. This subsequently stimulates immune response factors. Since the host immune response and severity of COVID-19 vary among individuals, genetic risk factors for severe COVID-19 cases have been investigated. Our research group recently conducted a survey of genetic variants among SARS-CoV-2-interacting molecules across populations, noting near absence of difference in allele frequency spectrum between populations in these genes. Recent genome-wide association studies have identified genetic risk factors for severe COVID-19 cases in a segment of chromosome 3 that involves six genes encoding three immune-regulatory chemokine receptors and another three molecules. The risk haplotype seemed to be inherited from Neanderthals, suggesting genetic adaptation against pathogens in modern human evolution. Therefore, SARS-CoV-2 uses highly conserved molecules as its virion interaction, whereas its immune response appears to be genetically biased in individuals to some extent. We herein review the molecular process of SARS-CoV-2 infection as well as our further survey of genetic variants of its related immune effectors. We also discuss aspects of modern human evolution.
• Two macrophages, osteoclasts and microglia: from development to pleiotropy.
  Ji-Won Lee; In-Hee Lee; Tadahiro Iimura; Sek Won Kong
  Bone research, 9, 1, 11, 11, 10 Feb. 2021, [Peer-reviewed], [Lead author], [International Magazine]
  English, Scientific journal, Tissue-resident macrophages are highly specialized to their tissue-specific microenvironments, activated by various inflammatory signals and modulated by genetic and environmental factors. Osteoclasts and microglia are distinct tissue-resident cells of the macrophage lineage in bone and brain that are responsible for pathological changes in osteoporosis and Alzheimer's disease (AD), respectively. Osteoporosis is more frequently observed in individuals with AD compared to the prevalence in general population. Diagnosis of AD is often delayed until underlying pathophysiological changes progress and cause irreversible damages in structure and function of brain. As such earlier diagnosis and intervention of individuals at higher risk would be indispensable to modify clinical courses. Pleiotropy is the phenomenon that a genetic variant affects multiple traits and the genetic correlation between two traits could suggest a shared molecular mechanism. In this review, we discuss that the Pyk2-mediated actin polymerization pathway in osteoclasts and microglia in bone and brain, respectively, is the horizontal pleiotropic mediator of shared risk factors for osteoporosis and AD.
• A survey of genetic variants in SARS-CoV-2 interacting domains of ACE2, TMPRSS2 and TLR3/7/8 across populations.
  In-Hee Lee; Ji-Won Lee; Sek Won Kong
  Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 85, 104507, 104507, Nov. 2020, [Peer-reviewed], [Lead author], [International Magazine]
  English, Scientific journal, The COVID-19 pandemic highlighted healthcare disparities in multiple countries. As such morbidity and mortality vary significantly around the globe between populations and ethnic groups. Underlying medical conditions and environmental factors contribute higher incidence in some populations and a genetic predisposition may play a role for severe cases with respiratory failure. Here we investigated whether genetic variation in the key genes for viral entry to host cells-ACE2 and TMPRSS2-and sensing of viral genomic RNAs (i.e., TLR3/7/8) could explain the variation in incidence across diverse ethnic groups. Overall, these genes are under strong selection pressure and have very few nonsynonymous variants in all populations. Genetic determinant for the binding affinity between SARS-CoV-2 and ACE2 does not show significant difference between populations. Non-genetic factors are likely to contribute differential population characteristics affected by COVID-19. Nonetheless, a systematic mutagenesis study on the receptor binding domain of ACE2 is required to understand the difference in host-viral interaction across populations.

  
  Download
• Teriparatide relieves ovariectomy-induced hyperalgesia in rats, suggesting the involvement of functional regulation in primary sensory neurons by PTH-mediated signaling.
  Tanaka T; Takao-Kawabata R; Takakura A; Shimazu Y; Nakatsugawa M; Ito A; Lee JW; Kawasaki; Iimura T
  Sci Rep., 10, 1, 5346, 24 Mar. 2020, [Peer-reviewed]
  English, Scientific journal
• The effects of resistance training on bone mineral density and bone quality in type 2 diabetic rats.
  Ikedo A; Kido K; Ato S; Sato K; Lee JW; Fujita S; Imai Y
  Physiological reports, 7, 6, e14046, Mar. 2019, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Resistance training (RT) has been known to be effective in maintaining and improving bone strength, which is based on bone mineral density (BMD) and bone quality. However, it is not clear whether RT is effective in improving bone strength in patients with type-2 diabetes mellitus (T2DM), who have a high risk of fracture. Therefore, we tested the effects of a 6-week RT regimen using percutaneous electrical stimulation in T2DM model rats, male Otsuka Long-Evans Tokushima Fatty (OLETF), and its control, Long-Evans Tokushima Otsuka (LETO). After 6 weeks of RT, tibial BMD in RT legs was significantly higher than that in control (CON) legs in both groups. In diaphyseal cortical bone, bone area/tissue area, and cortical thickness was significantly increased in RT legs compared with CON legs in both groups. Cortical porosity was highly observed in OLETF compared with LETO, but RT improved cortical porosity in both groups. Interestingly, trabecular number, trabecular thickness and trabecular space as well as BMD and bone volume/tissue volume in proximal tibial metaphyseal trabecular bone were significantly improved in RT legs compared with CON legs in both groups. In contrast, connectivity density and structural model index were not affected by RT. These results indicate that the 6-week RT regimen effectively increased BMD and improved bone quality in T2DM model rats as well as control rats. Therefore, RT may have the potential to improve bone strength and reduce fracture risk, even in patients with T2DM.
• Zscan10 suppresses osteoclast differentiation by regulating expression of Haptoglobin.
  Yanagihara Y; Inoue K; Saeki N; Sawada Y; Yoshida S; Lee JW; Iimura T; Imai Y
  Bone, 122, 93, 100, Feb. 2019, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Zinc finger and SCAN domain containing 10 (Zscan10) was identified as a novel transcription factor that is involved in osteoclast differentiation in our previous report. However, the biological functions of Zscan10 are not fully understood except its roles in the maintenance of genome stability and pluripotency of embryonic stem cells. Therefore, the purpose of this study was to clarify the function of Zscan10 in somatic cells, especially during osteoclast differentiation. First, Zscan10 KO RAW264 (KO) cells were established by genome editing using CRISPR/Cas9 and single cell sorting. Then, control (Ctrl) and KO cells were differentiated into osteoclasts by RANKL stimulation. We observed that TRAP activity and the expression levels of differentiation marker genes, such as Nfatc1, were significantly increased and the expression of inhibitory factors, such as Irf8, was decreased in KO cells compared to Ctrl cells. These results suggest that Zscan10 might regulate transcription of the genes that negatively control osteoclastogenesis. To understand gene expression profiles controlled by Zscan10, RNA-seq was performed and stringent analyses identified the haptoglobin gene (Hp) as a possible target of Zscan10. In addition, ChIP against Zscan10 revealed that Zscan10 could interact with its binding motif located near the Hp gene locus as well as the transcription start site of Hp, suggesting that Zscan10 can directly regulate transcription of Hp. Finally, to examine the effects of Hp on osteoclastogenesis, KO cells were treated with recombinant Hp (rHp). rHp treatment suppressed TRAP activity of KO cells without affecting cell viability. Furthermore, it has been reported that Hp KO mice exhibit decreased bone mass and increased osteoclast number. Importantly, hemolytic disease patients exhibited decreased serum level of Hp as well as low bone mineral density. Taken together, this study suggests that Zscan10 negatively regulates osteoclast differentiation through transcription of Hp.
• PV1, a novel Plasmodium falciparum merozoite dense granule protein, interacts with exported protein in infected erythrocytes.
  Masayuki Morita; Hikaru Nagaoka; Edward H Ntege; Bernard N Kanoi; Daisuke Ito; Takahiro Nakata; Ji-Won Lee; Kazuaki Tokunaga; Tadahiro Iimura; Motomi Torii; Takafumi Tsuboi; Eizo Takashima
  Scientific reports, 8, 1, 3696, 3696, 27 Feb. 2018, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Upon invasion, Plasmodium falciparum exports hundreds of proteins across its surrounding parasitophorous vacuole membrane (PVM) to remodel the infected erythrocyte. Although this phenomenon is crucial for the parasite growth and virulence, elucidation of precise steps in the export pathway is still required. A translocon protein complex, PTEX, is the only known pathway that mediates passage of exported proteins across the PVM. P. falciparum Parasitophorous Vacuolar protein 1 (PfPV1), a previously reported parasitophorous vacuole (PV) protein, is considered essential for parasite growth. In this study, we characterized PfPV1 as a novel merozoite dense granule protein. Structured illumination microscopy (SIM) analyses demonstrated that PfPV1 partially co-localized with EXP2, suggesting the protein could be a PTEX accessory molecule. Furthermore, PfPV1 and exported protein PTP5 co-immunoprecipitated with anti-PfPV1 antibody. Surface plasmon resonance (SPR) confirmed the proteins' direct interaction. Additionally, we identified a PfPV1 High-affinity Region (PHR) at the C-terminal side of PTP5 where PfPV1 dominantly bound. SIM analysis demonstrated an export arrest of PTP5ΔPHR, a PTP5 mutant lacking PHR, suggesting PHR is essential for PTP5 export to the infected erythrocyte cytosol. The overall results suggest that PfPV1, a novel dense granule protein, plays an important role in protein export at PV.
• 骨組織の顕微鏡研究.
  飯村忠浩; 李 智媛
  顕微鏡, 53, 24, 28, 2018, [Peer-reviewed], [Invited]
  Japanese, Scientific journal
• Higher Frequencies of Teriparatide develops Cortical Porosity.
  高倉綾; 高倉綾; LEE Ji-Won; 山根宏志; 高尾亮子; 飯村忠浩; 飯村忠浩; 飯村忠浩; 飯村忠浩
  日本骨形態計測学会雑誌, 28, 1, 31, 37, 2018, [Peer-reviewed], [Invited]
  Japanese, Scientific journal
• Uhrf1 is indispensable for normal limb growth by regulating chondrocyte differentiation through specific gene expression
  Michiko Yamashita; Kazuki Inoue; Noritaka Saeki; Maky Ideta-Otsuka; Yuta Yanagihara; Yuichiro Sawada; Iori Sakakibara; Jiwon Lee; Koichi Ichikawa; Yoshiaki Kamei; Tadahiro Iimura; Katsuhide Igarashi; Yasutsugu Takada; Yuuki Imai
  Development (Cambridge), 145, 1, Company of Biologists Ltd, 01 Jan. 2018, [Peer-reviewed]
  English, Scientific journal
• The HIV co-receptor CCR5 regulates osteoclast function
  Ji-Won Lee; Akiyoshi Hoshino; Kazuki Inoue; Takashi Saitou; Shunsuke Uehara; Yasuhiro Kobayashi; Satoshi Ueha; Kouji Matsushima; Akira Yamaguchi; Yuuki Imai; Tadahiro Iimura
  NATURE COMMUNICATIONS, 8, 1, 2226, Dec. 2017, [Peer-reviewed], [Lead author, Corresponding author]
  English, Scientific journal
• Administration frequency as well as dosage of PTH are associated with development of cortical porosity in ovariectomized rats
  Aya Takakura; Ji-Won Lee; Kyoko Hirano; Yukihiro Isogai; Toshinori Ishizuya; Ryoko Takao-Kawabata; Tadahiro Iimura
  BONE RESEARCH, 5, 17002, 17002, Apr. 2017, [Peer-reviewed], [International Magazine]
  English, Scientific journal
• Acute development of cortical porosity and endosteal naive bone formation from the daily but not weekly short-term administration of PTH in rabbit
  Hiroshi Yamane; Aya Takakura; Yukari Shimadzu; Toshiyuki Kodama; Ji-Won Lee; Yukihiro Isogai; Toshinori Ishizuya; Ryoko Takao-Kawabata; Tadahiro Iimura
  PLOS ONE, 12, 4, e0175329, Apr. 2017, [Peer-reviewed]
  English, Scientific journal
• Shedding quantitative fluorescence light on novel regulatory mechanisms in skeletal biomedicine and biodentistry.
  Lee JW; Iimura T
  Jpn Dent Sci Rev., 53, 53, 2, 10, Feb. 2017, [Peer-reviewed], [Invited]
  English, Digitalized fluorescence images contain numerical information such as color (wavelength), fluorescence intensity and spatial position. However, quantitative analyses of acquired data and their validation remained to be established. Our research group has applied quantitative fluorescence imaging on tissue sections and uncovered novel findings in skeletal biomedicine and biodentistry. This review paper includes a brief background of quantitative fluorescence imaging and discusses practical applications by introducing our previous research. Finally, the future perspectives of quantitative fluorescence imaging are discussed.
• アプライド・イメージング 先進イメージングによる生命医学のブレークスルー マルチモーダル超解像法を用いた骨系細胞の機能解析
  飯村 忠浩; 李 智媛
  Journal of Oral Biosciences Supplement, 2016, 70, 70, (一社)歯科基礎医学会, Sep. 2016
  Japanese
• 硬組織の形態・機能解析のための光学顕微鏡のマルチモードな活用法 微分干渉から先進レーザー顕微鏡の応用例
  飯村 忠浩; 李 智媛
  Journal of Oral Biosciences Supplement, 2016, 86, 86, (一社)歯科基礎医学会, Sep. 2016
  Japanese
• 機能と形態の統合的アプローチによる血管・唾液腺・骨の共創的研究 機能的生細胞イメージングとオミクス解析による破骨細胞調節機能の解明(Unveiling novel regulatory mechanisms of osteoclasts by combinatorial approaches of functional live-imaging and molecular omics)
  李 智媛; 飯村 忠浩
  Journal of Oral Biosciences Supplement, 2016, 139, 139, (一社)歯科基礎医学会, Sep. 2016
  English
• 骨細胞の機能と形態のヘテロジェニティ
  李 智媛; 飯村 忠浩
  THE BONE, 29, 3, 213, 218, (株)メディカルレビュー社, Oct. 2015, [Lead author]
  Japanese
• 骨の細胞イメージング-a new horizon-骨のメカニズムをどこまで観ることができるか 蛍光細胞イメージングと骨形態計測で見る骨代謝におけるケモカインシグナルの役割
  李 智媛; 飯村 忠浩
  Journal of Oral Biosciences Supplement, 2015, 100, 100, (一社)歯科基礎医学会, Sep. 2015
  Japanese
• Quantitative in situ fluorescence imaging to unveil the morphological and functional heterogeneity of osteocytes
  Ji-Won Lee; Tadahiro Iimura
  Journal of Oral Biosciences, 57, 2, 76, 79, Japanese Association for Oral Biology, 01 May 2015, [Peer-reviewed], [Lead author]
  English, Scientific journal
• Rosmarinic acid exerts an antiosteoporotic effect in the RANKL-induced mouse model of bone loss by promotion of osteoblastic differentiation and inhibition of osteoclastic differentiation
  Ji-Won Lee; Midori Asai; Sang-Kyung Jeon; Tadahiro Iimura; Takayuki Yonezawa; Byung-Yoon Cha; Je-Tae Woo; Akira Yamaguchi
  MOLECULAR NUTRITION & FOOD RESEARCH, 59, 3, 386, 400, Mar. 2015, [Peer-reviewed], [Lead author]
  English, Scientific journal
• Changes in the spatial distribution of sclerostin in the osteocytic lacuno-canalicular system in alveolar bone due to orthodontic forces, as detected on multimodal confocal fluorescence imaging analyses
  Yuriko Nishiyama; Tsutomu Matsumoto; Ji-Won Lee; Takashi Saitou; Takeshi Imamura; Keiji Moriyama; Akira Yamaguchi; Taclahiro Iimura
  ARCHIVES OF ORAL BIOLOGY, 60, 1, 45, 54, Jan. 2015, [Peer-reviewed], [International Magazine]
  English, Scientific journal
• A possible role of DMP1 as a negative regulator of FGF23 production in functional heterogeneity osteocytes: Three-dimensional morphological approaches.
  Lee Ji-Won; Yamaguchi Akira; Iimura Tadahiro
  JOURNAL OF BONE AND MINERAL RESEARCH, 29, S171, Feb. 2014, [Peer-reviewed], [Lead author]
• Functional heterogeneity of osteocytes in FGF23 production: the possible involvement of DMP1 as a direct negative regulator.
  Lee JW; Yamaguchi A; Iimura T
  BoneKEy reports, 3, 543, 543, 2014, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Fibroblast growth factor 23 (FGF23) and dentin matrix protein (DMP1) are hallmarks of osteocytes in bone. However, the mechanisms underlying the actions of DMP1 as a local factor regulating FGF23 and bone mineralization are not well understood. We first observed spatially distinct distributions of FGF23- and DMP1-positive osteocytic lacunae in rat femurs using immunohistochemistry. Three-dimensional immunofluorescence morphometry further demonstrated that the distribution and relative expression levels of these two proteins exhibited reciprocally reversed patterns especially in midshaft cortical bone. These in vivo findings suggest a direct role of DMP1 in FGF23 expression in osteocytes. We next observed that the inoculation of recombinant DMP1 in UMR-106 osteoblast/osteocyte-like cells and long-cultured MC3T3-E1 osteoblastic cells showed significant downregulation of FGF23 production. This effect was rescued by incubation with an focal adhesion kinase (FAK) inhibitor or MEK (mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK)) inhibitor but not inhibitors of phosphoinositide 3-kinase or Rho kinase. Consistently, the levels of phosphorylated FAK, ERK and p38 were significantly elevated, indicating that exogenous DMP1 is capable of activating FAK-mediated MAPK signaling. These findings suggest that DMP1 is a local, direct and negative regulator of FGF23 production in osteocytes involved in the FAK-mediated MAPK pathway, proposing a relevant pathway that coordinates the extracellular environment of osteocytic lacunae and bone metabolism.
• RANKL synthesized by both stromal cells and cancer cells plays a crucial role in osteoclastic bone resorption induced by oral cancer.
  Kiyoshi Sato; Ji-Won Lee; Kei Sakamoto; Tadahiro Iimura; Kou Kayamori; Hisataka Yasuda; Masanobu Shindoh; Masako Ito; Ken Omura; Akira Yamaguchi
  Am. J. Pathol., 182, 5, 1890, 1899, May 2013, [Peer-reviewed]
  English, The molecular mechanisms underlying bone destruction by invading oral cancer are not well understood. Using IHC, we demonstrated that receptor activator of nuclear factor-κB ligand (RANKL)-positive fibroblasts and cancer cells were located at sites of bone invasion in human oral cancers. HSC3 and HO-1-N-1, human oral cancer cell lines, expressed RANKL and stimulated Rankl expression in the UAMS-32 murine osteoblastic cell line. We discriminated the roles of RANKL synthesized by stromal cells and cancer cells in cancer-associated bone resorption by using species-specific RANKL antibodies against murine RANKL and human RANKL, respectively. Osteoclastogenesis induced by the conditioned medium of HSC3 and HO-1-N-1 cells in a co-culture of murine bone marrow cells and UAMS-32 cells was inhibited by the addition of antibodies against either mouse or human RANKL. HSC3-induced bone destruction was greatly inhibited by the administration of anti-mouse RANKL antibody in a xenograft model. HO-1-N-1-induced bone destruction was inhibited by the administration of either anti-mouse or anti-human RANKL antibody. Bone destruction induced by the transplantation of human RANKL-overexpressing cells
• RANKL Synthesized by Both Stromal Cells and Cancer Cells Plays a Crucial Role in Osteoclastic Bone Resorption Induced by Oral Cancer
  Kiyoshi Sato; Ji-Won Lee; Kei Sakamoto; Tadahiro Iimura; Kou Kayamori; Hisataka Yasuda; Masanobu Shindoh; Masako Ito; Ken Omura; Akira Yamaguchi
  AMERICAN JOURNAL OF PATHOLOGY, 182, 5, 1890, 1899, May 2013, [Peer-reviewed]
  English, Scientific journal
• CXCL2 synthesized by oral squamous cell carcinoma is involved in cancer-associated bone destruction
  Erika Oue; Ji-Won Lee; Kei Sakamoto; Tadahiro Iimura; Kazuhiro Aoki; Kou Kayamori; Yasuyuki Michi; Masashi Yamashiro; Kiyoshi Harada; Teruo Amagasa; Akira Yamaguchi
  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 424, 3, 456, 461, Aug. 2012, [Peer-reviewed]
  English, Scientific journal
• Effects of veraguensin and galgravin on osteoclast differentiation and function
  Midori Asai; Ji-Won Lee; Yasunori Itakura; Bong-Keun Choi; Takayuki Yonezawa; Toshiaki Teruya; Byung-Yoon Cha; Motoko Ohnishi; Akira Yamaguchi; Je-Tae Woo
  CYTOTECHNOLOGY, 64, 3, 315, 322, May 2012, [Peer-reviewed]
  English, Scientific journal
• Coptisine inhibits RANKL-induced NF-kappa B phosphorylation in osteoclast precursors and suppresses function through the regulation of RANKL and OPG gene expression in osteoblastic cells
  Ji-Won Lee; Ayumi Iwahashi; Shin-ichi Hasegawa; Takayuki Yonezawa; Won Bae Jeon; Byung-Yoon Cha; Kazuo Nagai; Je-Tae Woo
  JOURNAL OF NATURAL MEDICINES, 66, 1, 8, 16, Jan. 2012, [Peer-reviewed], [Lead author]
  English, Scientific journal
• Osteogenic activity of diphenyl ether-type cyclic diarylheptanoids derived from Acer nikoense
  Takayuki Yonezawa; Ji-Won Lee; Hiroyuki Akazawa; Masahiko Inagaki; Byung-Yoon Cha; Kazuo Nagai; Kazumi Yagasaki; Toshihiro Akihisa; Je-Tae Woo
  BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 21, 11, 3248, 3251, Jun. 2011, [Peer-reviewed]
  English, Scientific journal
• Harmine promotes osteoblast differentiation through bone morphogenetic protein signaling
  Takayuki Yonezawa; Ji-Won Lee; Ayaka Hibino; Midori Asai; Hironori Hojo; Byung-Yoon Cha; Toshiaki Teruya; Kazuo Nagai; Ung-Il Chung; Kazumi Yagasaki; Je-Tae Woo
  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 409, 2, 260, 265, Jun. 2011, [Peer-reviewed]
  English, Scientific journal
• Acerogenin A, a natural compound isolated from Acer nikoense Maxim, stimulates osteoblast differentiation through bone morphogenetic protein action
  Tasuku Kihara; Saki Ichikawa; Takayuki Yonezawa; Ji-Won Lee; Toshihiro Akihisa; Je Tae Woo; Yasuyuki Michi; Teruo Amagasa; Akira Yamaguchi
  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 406, 2, 211, 217, Mar. 2011, [Peer-reviewed]
  English, Scientific journal
• Palmatine Attenuates Osteoclast Differentiation and Function through Inhibition of Receptor Activator of Nuclear Factor-kappa B Ligand Expression in Osteoblast Cells
  Ji-Won Lee; Naomi Mase; Takayuki Yonezawa; Hwa-Jeong Seo; Won Bae Jeon; Byung Yoon Cha; Kazuo Nagai; Je-Tae Woo
  BIOLOGICAL & PHARMACEUTICAL BULLETIN, 33, 10, 1733, 1739, Oct. 2010, [Peer-reviewed], [Lead author]
  English, Scientific journal
• Alisol-B, a novel phyto-steroid, suppresses the RANKL-induced osteoclast formation and prevents bone loss in mice
  Ji-Won Lee; Yasuhiro Kobayashi; Yuko Nakamichi; Nobuyuki Udagawa; Naoyuki Takahashi; Nam-Kyung Im; Hwa-Jeong Seo; Won Bae Jeon; Takayuki Yonezawa; Byung-Yoon Cha; Je-Tae Woo
  BIOCHEMICAL PHARMACOLOGY, 80, 3, 352, 361, Aug. 2010, [Peer-reviewed], [Lead author]
  English, Scientific journal
• Inhibitory effect of luteolin on osteoclast differentiation and function
  Ji-Won Lee; Jae-Yong Ahn; Shin-ichi Hasegawa; Byung-Yoon Cha; Takayuki Yonezawa; Kazuo Nagai; Hwa-Jeong Seo; Won-Bae Jeon; Je-Tae Woo
  CYTOTECHNOLOGY, 61, 3, 125, 134, Dec. 2009, [Peer-reviewed], [Lead author]
  English, Scientific journal
• Antimicrobial effect and resistant regulation of Glycyrrhiza uralensis on methicillin-resistant Staphylococcus aureus
  Ji-Won Lee; Young-Ju Ji; Mi-Hee Yu; Mi-Hyang Hwang Bo; Hwa-Jeong Seo; Sam-Pin Lee; In-Seon Lee
  NATURAL PRODUCT RESEARCH, 23, 2, 101, 111, 2009, [Peer-reviewed], [Lead author]
  English, Scientific journal
• Bone-protecting effect of Rubus coreanus by dual regulation of osteoblasts and osteoclasts
  Sun Hee Do; Ji-Won Lee; Wong-Il Jeong; Jae-Yong Chung; Sang-Joon Park; Il-Hwa Hong; Sang Kyung Jeon; In-Seon Lee; Kyu-Shik Jeong
  MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY, 15, 4, 676, 683, Jul. 2008, [Peer-reviewed]
  English, Scientific journal
• Effects of Rubus coreanus Miquel extracts on the proliferation and differentiation of mouse osteoblast-like MC3T3-E1 cells
  Ji-Won Lee; In-Seon Lee
  JOURNAL OF FOOD AND DRUG ANALYSIS, 16, 1, 80, 87, Feb. 2008, [Peer-reviewed], [Lead author]
  English, Scientific journal
• Effects of ethanol extract from Saururus chinensis (Bour.) Baill on lipid and antioxidant metabolisms in rats fed a high-fat diet
  Mi Hee Yu; Hyo Gwon Im; Ji-Won Lee; Mi-Hyang Hwang Bo; Hyun-Jeong Kim; Suk Kyung Kim; Shin Kyo Chung; In-Seon Lee
  NATURAL PRODUCT RESEARCH, 22, 3, 275, 283, 2008, [Peer-reviewed]
  English, Scientific journal
• Effect of Saliva miltiorrhiza Bunge on antimicrobial activity and resistant gene regulation against methicillin-resistant staphylococcus aureus (MRSA)
  Ji-Won Lee; Young-Ju Ji; Syng-Ook Lee; In-Seon Lee
  JOURNAL OF MICROBIOLOGY, 45, 4, 350, 357, Aug. 2007, [Peer-reviewed], [Lead author]
  English, Scientific journal
• Antioxidative and cytoprotective effects of Artemisia capillaris fractions
  Jung-Hee Hong; Ji-Won Lee; Jung-Hyun Park; In-Seon Lee
  BIOFACTORS, 31, 1, 43, 53, 2007, [Peer-reviewed]
  English, Scientific journal
• ENA Actimineral Resource A restores bone loss and bone quality in ovariectomized rats
  Sun Hee Do; Sung-Yong Hwa; Won-Il Jeong; Ji-Won Lee; Hyun-Jung Kim; In-Seon Lee; Kyu-Shik Jeong
  MOLECULAR AND CELLULAR BIOCHEMISTRY, 295, 1-2, 35, 43, Jan. 2007, [Peer-reviewed]
  English, Scientific journal
• Wogonin suppresses TNF-alpha-induced MMP-9 expression by blocking the NF-kappa B activation via MAPK signaling pathways in human aortic smooth muscle cells
  Syng-Ook Lee; Yun-Jeong Jeong; Mi Hee Yu; Ji-Won Lee; Mi Hyang Hwangbo; Cheorl-Ho Kim; In-Seon Lee
  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 351, 1, 118, 125, Dec. 2006, [Peer-reviewed]
  English, Scientific journal

• CCR5を介した細胞中心体のクラスタリングが破骨細胞の骨吸収機能を調節する。
  李智媛; LEE In-Hee; WATANABE Haruhisa; MAEKAWA Masashi; UEHARA Shunsuke; KOBAYASHI Yasuhiro; IMAI Yuuki; IMAI Yuuki; KONG Sek Won; KONG Sek Won; IIRNURA Tadahiro, 日本骨代謝学会学術集会プログラム抄録集(CD-ROM), 42nd, 2024
• RAW264.7細胞においてCalcitriolがアポトーシスを誘導する
  笠井 満知子; 中村 圭佑; 李 智媛; 長谷部 晃, Journal of Oral Biosciences Supplement, 2023, [P1, 03], Sep. 2023
  (一社)歯科基礎医学会, Japanese
• Candida albicans臨床分離株の抗真菌薬感受性の比較・検討
  中村 圭佑; 笠井 満知子; 李 智媛; 長谷部 晃, Journal of Oral Biosciences Supplement, 2023, [P1, 33], Sep. 2023
  (一社)歯科基礎医学会, Japanese
• 骨形態計測研究の新展開-新時代を拓く若手女性研究者たち CCR5を介した細胞の極性調節における中心体クラスター形成の役割(The role of centrosome clustering in CCR5-medaited cell polarity)
  李 智媛; 飯村 忠浩, 日本骨形態計測学会雑誌, 33, 1, 118, 118, May 2023
  日本骨形態計測学会, English
• 破骨細胞の分化成熟におけるPyk2の役割
  西浦 まい; 八若 保孝; 飯村 忠浩; 李 智媛, 日本骨形態計測学会雑誌, 33, 1, 197, 197, May 2023
  日本骨形態計測学会, Japanese
• 女性における顎関節の退行性病変の病態と血清CCL5値の上昇との関連性
  渡辺陽久; 庵敬; 李智媛; 梶井貴史; 高倉綾; 高尾亮子; 北川善政; 丸岡豊; 飯村忠浩, 日本骨形態計測学会雑誌, 33, 1, 2023
• 最新の歯学 骨格痛における感覚神経節マクロファージの病態機能と創薬展開
  庵 敬; 佐藤 孝紀; 李 智媛; 北川 善政; 飯村 忠浩, 北海道歯学雑誌, 43, 2, 4, Sep. 2022
  骨・関節の障害に由来する慢性疼痛は骨格痛と呼ばれ、骨粗鬆症、変形性関節症、転移性骨腫瘍など多様な疾患群によって引き起こされる。脊髄後根神経節(DRG)は骨格系の一次求心性の神経細胞体が集合する感覚神経節である。近年、骨格痛の発症・遷延にはDRGにおけるマクロファージの活性化やそれに付随して生じる神経炎症が関わっていることが明らかになった。炎症性マクロファージ抑制や神経炎症をターゲットとした新規治療薬の創薬について述べた。, 北海道歯学会, Japanese
• AI-駆動型蛍光形態計測によるPTH製剤の骨微細構造および骨コラーゲン整調効果の解明
  佐藤 孝紀; 高倉 綾; 李 智媛; 高尾 亮子; 飯村 忠浩, 日本骨形態計測学会雑誌, 32, 1, S168, S168, May 2022
  日本骨形態計測学会, Japanese
• 3次元蛍光イメージングによる脳のミクログリア貪食能の定量評価法の確立
  渡辺陽久; 渡辺陽久; 李智媛; 北川善政; 飯村忠浩, 日本顕微鏡学会北海道支部学術講演会講演要旨集, 2022 (CD-ROM), 2022
• 3次元蛍光イメージングによる骨粗鬆症誘導性神経炎症の解析
  庵敬; 庵敬; 渡辺陽久; 渡辺陽久; 李智媛; 北川善政; 飯村忠浩, 日本顕微鏡学会北海道支部学術講演会講演要旨集, 2022 (CD-ROM), 2022
• SARS-CoV-2感染マウスを用いた肺血管内皮細胞の重症化関連遺伝子の解析
  武田遼; 武田遼; 伊藤航; 手代木孝仁; 佐々木道仁; 大場靖子; 大場靖子; 間石奈湖; 松田彩; 佐藤彰彦; 鳥羽晋輔; 李智媛; 飯村忠浩; 樋田泰浩; 北川善政; 澤洋文; 澤洋文; 澤洋文; 樋田京子, 日本血管生物医学会学術集会プログラム・抄録集, 30th (CD-ROM), 1, 219, 219, 2022
  (一社)日本病理学会, Japanese
• 骨粗鬆症治療薬PTH製剤による骨微細構造および骨コラーゲンの整調効果の解明 新規蛍光イメージング解析による定量的トポロジー解析による骨質評価法の確立(Teriparatide administration harmonizes the arrangement of bone collagen and bone microstructure: a novel fluorescence analysis to evaluate bone quality)
  佐藤 孝紀; 李 智媛; 飯村 忠浩; 高倉 綾; 高尾 亮子; 徳永 和明; 松森 はるか, Journal of Oral Biosciences Supplement, 2021, 154, 154, Oct. 2021
  (一社)歯科基礎医学会, Japanese
• 新規蛍光形態計測法および第2次高調波イメージングによる骨粗鬆症治療薬PTH製剤による骨質改善効果の定量評価法の確立
  佐藤孝紀; 李智媛; 飯村忠浩, 日本顕微鏡学会北海道支部学術講演会講演要旨集, 2021 (CD-ROM), 2021
• Teriparatide administration harmonizes the arrangement of bone collagen and bone microstructure-a novel fluorescence analysis to evaluate bone quality-
  佐藤孝紀; LEE JW; 飯村忠浩, Journal of Oral Biosciences Supplement (Web), 2021, 2021
• 最新の歯学 HIV感染と骨吸収性疾患をつなぐ新規骨免疫学的薬理学的作用
  佐藤 孝紀; 戸井田 侑; 服部 倫寛; 李 智媛; 飯村 忠浩, 北海道歯学雑誌, 41, 1, 27, 29, Sep. 2020
  北海道歯学会, Japanese
• ラット骨粗鬆症性痛覚過敏に対するテリパラチドの薬理作用の解明-蛍光形態計測と分子オミクスによる解析-
  田中智哉; 田中智哉; 高倉綾; 高倉綾; 高尾亮子; 李智媛; 飯村忠浩, 日本骨形態計測学会雑誌, 30, 1, 2020
• 日本と韓国の骨代謝研究における基礎・臨床の最近のトピックス HIV共受容体CCR5は破骨細胞の機能調節を介して骨吸収性疾患に関与する
  李 智媛, 日本骨代謝学会学術集会プログラム抄録集, 36回, 102, 102, Jul. 2018
  (一社)日本骨代謝学会, English
• マルチモード蛍光観察による新規の骨代謝病態機能探索
  飯村忠浩; 李智媛, 日本解剖学会総会・全国学術集会講演プログラム・抄録集, 123rd, 2018
• 新規デンスグラニュールタンパク質PV1のマラリア原虫感染赤血球内タンパク質輸送における機能
  森田将之; 高島英造; 長岡ひかる; NTEGE Edward H.; KANOI Bernard N.; 伊藤大輔; LEE Ji-Won; 徳永和明; 飯村忠浩; 鳥居本美; 坪井敬文, 日本寄生虫学会大会プログラム・抄録集, 87th, 2018
• Zscan10はHaptoglobinの転写を介して破骨細胞分化を負に制御する
  柳原裕太; 柳原裕太; 井上和樹; 井上和樹; 佐伯法学; 佐伯法学; 沢田雄一郎; 沢田雄一郎; LEE Jiwon; 飯村忠浩; 飯村忠浩; 今井祐記; 今井祐記, 日本骨代謝学会学術集会プログラム抄録集, 36th, 2018
• 骨疾患の病態解明と新たな治療法開発への基礎的アプローチ マウスジェネティクスを用いたHIV感染患者の骨病態解明
  飯村 忠浩; 李 智媛, Journal of Oral Biosciences Supplement, 2017, 111, 111, Sep. 2017
  (一社)歯科基礎医学会, Japanese
• Unveiling a rhythmic regulatory mode hidden in developmental tissue growth by fluorescence live imaging-based mathematical modeling
  Tadahiro Iimura; Ji-Won Lee, Journal of Oral Biosciences, 59, 1, 6, 11, 01 Feb. 2017
  Japanese Association for Oral Biology, English, Book review
• 骨形態計測法で明らかになったHIV治療薬標的分子CCR5の破骨細胞機能分化における必須の機能
  李智媛; 飯村忠浩; 飯村忠浩; 飯村忠浩; 飯村忠浩, 日本骨形態計測学会雑誌, 27, 1, 2017
• テリパラチドによる皮質骨空隙形成は投与頻度に依存する~卵巣摘除ラットのマルチスケール骨形態解析~
  高倉綾; 高倉綾; 李智媛; 高尾亮子; 飯村忠浩; 飯村忠浩; 飯村忠浩; 飯村忠浩, 日本骨形態計測学会雑誌, 27, 1, 2017
• マウスジェネティクスを用いたHIV感染患者の骨病態解明
  飯村忠浩; 飯村忠浩; 飯村忠浩; LEE J-W, Journal of Oral Biosciences Supplement (Web), 2017, 2017
• 高頻度のテリパラチド投与は皮質骨空隙形成を誘発する。-卵巣摘除ラットでの検討-
  高倉綾; 高倉綾; LEE Ji-Won; 高尾亮子; 飯村忠浩; 飯村忠浩; 飯村忠浩; 飯村忠浩, 日本骨代謝学会学術集会プログラム抄録集, 35th, 2017
• 赤血球内タンパク質輸送に関わる新規デンスグラニュールタンパク質PV1の機能解析
  森田将之; 高島英造; 長岡ひかる; KANOI Bernard N.; 伊藤大輔; THONGKUKIATKUL Amporn; 李智媛; 徳永和明; 飯村忠浩; 鳥居本美; 坪井敬文, 日本寄生虫学会大会プログラム・抄録集, 86th, 2017
• エピゲノム制御因子Uhrf1によるDNAメチル化制御を介した軟骨分化・骨格形成
  山下美智子; 山下美智子; 井上和樹; 井上和樹; 佐伯法学; 佐伯法学; 榊原伊織; LEE Jiwon; 大塚まき; 亀井義明; 五十嵐勝秀; 高田泰次; 飯村忠浩; 飯村忠浩; 今井祐記, 日本骨代謝学会学術集会プログラム抄録集, 35th, 2017
• HIV治療薬標的分子CCR5の破骨細胞機能分化における必須の機能-CCR5を標的としたHIV治療は骨吸収性疾患に対してもメリットをもたらす可能性がある
  LEE Ji-Won; 上原俊介; 小林泰浩; 山口朗; 今井祐記; 飯村忠浩; 飯村忠浩; 飯村忠浩; 飯村忠浩, 日本骨代謝学会学術集会プログラム抄録集, 35th, 2017
• 破骨細胞の構造学的な機能におけるケモカインを介したシグナル伝達系の役割(Rising Stars in Skeletal Biology Roles of Chemokine-mediated signaling in architectural function of osteoclasts)
  李 智媛; 星野 昭芳; 井上 和樹; 上原 俊介; 小林 泰浩; 山口 朗; 今井 祐記; 飯村 忠浩, 日本骨代謝学会学術集会プログラム抄録集, 34回, 130, 130, Jul. 2016
  (一社)日本骨代謝学会, English
• マルチモーダル超解像法を用いた骨系細胞の機能解析
  飯村忠浩; 飯村忠浩; 飯村忠浩; 飯村忠浩; LEE J-W, Journal of Oral Biosciences Supplement (Web), 2016, 2016
• 硬組織の形態・機能解析のための光学顕微鏡のマルチモードな活用法-微分干渉から先進レーザー顕微鏡の応用例-
  飯村忠浩; 飯村忠浩; 飯村忠浩; 飯村忠浩; LEE J-W, Journal of Oral Biosciences Supplement (Web), 2016, 2016
• マルチスケール画像解析の骨生物医学への応用展開
  飯村忠浩; 飯村忠浩; 飯村忠浩; 飯村忠浩; 李智媛, 日本骨形態計測学会雑誌, 25, 2, 2015
• DMP1は骨細胞におけるFGF23産生の抑制因子である-蛍光3次元形態計測と細胞生物学的アプローチ-
  李智媛; 李智媛; 山口朗; 飯村忠浩; 飯村忠浩; 飯村忠浩; 飯村忠浩, 日本骨代謝学会学術集会プログラム抄録集, 32nd, 2014
• 口腔癌による骨破壊では間質細胞と癌細胞の両者が産生するRANKLが重要である
  佐藤潔; 李智媛; 飯村忠浩; 保田尚孝; 伊東昌子; 小村健; 山口朗, 日本骨代謝学会学術集会プログラム抄録集, 30th, 2012

• Morphological plasticity and functional regulation in osteoclasts and microglia
  Ji-Won Lee
  Japanese Society of Bone Mineral Research, 25 Jul. 2025, Oral presentation
  24 Jul. 2025 - 26 Jul. 2025, [Invited]
• CCR5 signaling pathways modulate centrosome clustering in osteoclasts
  Ji-Won Lee
  Japan Bone Academy, 08 Dec. 2024, Invited oral presentation
  07 Dec. 2024 - 08 Dec. 2024, [Invited]
• Potential Bio-Signal: Links between osteoporosis and Alzheimer’s disease
  第66回歯科基礎医学会学術大会, 01 Nov. 2024, Oral presentation
  01 Nov. 2024 - 03 Nov. 2024, [Invited]
• Intersection Pathways: Chronic Periodontitis, Cognitive Decline, and Emerging Therapeutic Frontiers
  Ji-Won Lee
  第98回日本細菌学会総会, 09 Aug. 2024, Oral presentation
  07 Aug. 2024 - 09 Aug. 2024, [Invited]
• The role of centrosome clustering in CCR5-mediated cell polarity
  Ji-Won Lee
  第43回日本骨形態計測学会, 30 Jun. 2023, Oral presentation
  29 Jun. 2023 - 01 Jul. 2023, [Invited]
• Potential Bio-Signal Links: between osteoporosis and Alzheimer’s disease
  Ji-Won Lee
  第60回日本口腔科学会北日本地方部会・第48回日本口腔外科学会北日本支部学術集会, 09 Jul. 2022, Oral presentation
  09 Jul. 2022 - 10 Jul. 2022, [Invited]
• CCR5 is required for osteoclast function through regulating lysosomal vesicle trafficking
  Lee Ji-Won
  The American Society for Bone and Mineral Research, 28 Sep. 2018, English, Poster presentation
  [International presentation]
• Osteoclast function and cytoskeletal configuration
  Lee Ji-Won
  Protein Island Matsuyama (PIM) International Symposium, 12 Sep. 2018, English, Invited oral presentation
  [Invited], [International presentation]
• 骨形態計測法で明らかになったHIV治療薬標的分子CCR5の破骨細胞機能分化における必須の機能
  Lee Ji-Won
  第３７回日本骨形態計測学会, 23 Jun. 2017, English, Oral presentation
  [Invited], [Domestic Conference]
• CCR5, a co-receptor of HIV, is required for the functional cellular architecture of osteoclasts, unveiling the direct association between loss of CCR5 and resistance to bone loss in mice
  Lee Ji-Won
  Australian and New Zealand Bone and Mineral Society, 17 Jun. 2017, English, Poster presentation
  [International presentation]
• Novel regulatory mechanisms of osteoclast function, as revealed by combinatorial approaches of functional live-imaging and molecular omics
  Lee Ji-Won
  The 39th Annual Meeting of the Molecular Biology Society of Japan, 01 Dec. 2016, English, Oral presentation
  [Invited], [Domestic Conference]
• Requirement of CCR5, a co-receptor of HIV, for the functional cellular architecture of osteoclasts, providing experimental evidence for the direct association between loss of CCR5 and resistance to bone loss
  Lee Ji-Won
  6th Asia-Pacific Osteoporosis Meeting, 04 Nov. 2016, English, Poster presentation
  [International presentation]
• Unveiling novel regulatory mechanisms of osteoclasts by integrative approaches of bio-imaging and molecular omics
  Lee Ji-Won
  Protein Island Matsuyama (PIM) International Symposium, 16 Sep. 2016, English, Invited oral presentation
  [Invited], [International presentation]
• Role of chemokine-mediated signaling in architectural function of osteoclasts
  Lee Ji-Won
  The 34th Annual meeting of Japanese Society for Bone and Mineral Research, 22 Jul. 2016, English, Oral presentation
  [Invited], [Domestic Conference]
• C-C chemokine receptor 5, a co-receptor of HIV, -mediated signal is required for geometric architecture and function of osteoclasts, thus for RANKL-induced bone destruction
  Lee Ji-Won
  43rd Annual European Calcified Tissue Society Congress, 14 May 2016, English, Poster presentation
  [International presentation]
• C-C chemokine receptor 5, a co-recpetor of HIV, -mediated signal regulates bone resorption via locomotion of osteoclasts
  Lee Ji-Won
  The American Society for Bone and Mineral Research, 09 Oct. 2015, English, Poster presentation
  [International presentation]
• Quantitative illumination on bone histology and cell biology by fluorescence imaging
  Lee Ji-Won
  International Symposium on Bio-Imaging and Gene Targeting Sciences, 15 Feb. 2015, English, Invited oral presentation
  [Invited], [International presentation]
• Cell cycler phase-dependent phosphorylation of Smads in skeletal cells
  Lee Ji-Won
  10th International BMP conference, 16 Sep. 2014, English, Poster presentation
  [International presentation]
• A possible role of DMP1 as a negative regulator of FGF23 production in functional heterogeneity osteocytes: Three-dimensional morphological approaches
  Lee Ji-Won
  The American Society for Bone and Mineral Research, 12 Sep. 2014, English, Poster presentation
  [International presentation]
• Acerogenins, a natural compound isolated from Acer nikoense Maxim. Stimulates osteoblast differentiation through bone morphogenetic protein action
  Lee Ji-Won
  The American Society for Bone and Mineral Research, 16 Sep. 2011, English, Poster presentation
  [International presentation]
• Isoquinoline alkaloids attenuate osteoclast differentiation and function through regulation of RANKL and OPG gene expression in osteoblastic cells
  Lee Ji-Won
  The American Society for Bone and Mineral Research, 15 Oct. 2010, Japanese, Poster presentation
  [International presentation]
• Biological effects of cyclic diarypheptanoids on tooth root formation
  Lee Ji-Won
  10th Tooth Morphogenesis and Differentiation, 01 Sep. 2010, English, Poster presentation
  [International presentation]

• 口腔感染制御学, 2024年, 博士後期課程, 歯学院
• 口腔感染制御学研究, 2024年, 博士後期課程, 歯学院
• 英語演習, 2024年, 学士課程, 全学教育
• 微生物学・口腔微生物学実習, 2024年, 学士課程, 歯学部
• 微生物学・口腔微生物学Ⅰ, 2024年, 学士課程, 歯学部
• 微生物学・口腔微生物学Ⅱ, 2024年, 学士課程, 歯学部
• アクティブラーニング科目Ⅳ, 2024年, 学士課程, 歯学部

• ヨロピアンcalcified tissue society
• アメリカン骨代謝学会
• 日本歯科基礎学会
• JAPANESE SOCIETY FOR BONE MORPHOMETRY
• JAPANESE SOCIETY FOR BONE AND MINERAL RESEARCH

• Pharmacological study of a shared genetic risk factor for osteoporosis and Alzheimer's disease
  Grants-in-Aid for Scientific Research
  Apr. 2023 - Mar. 2026
  研究代表者; 李智媛; 研究分担者; 飯村忠浩
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 23K09116
• A drug development study for radiation osteonecrosis of jaw with improving micro vascular-skeletal structure
  Grants-in-Aid for Scientific Research
  30 Jun. 2023 - 31 Mar. 2025
  飯村 忠浩; 丸岡 豊; 樋田 京子; 李 智媛
  Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Research (Exploratory), Hokkaido University, 23K18347
• Investigation of chromatic remodeling in osteoclast function for therapeutic targeting of bone remodeling balance
  Grants-in-Aid for Scientific Research
  01 Apr. 2019 - 31 Mar. 2023
  李 智媛
  In this research, we investigated the functional role of epigenetic chromatin remodeler, BAF155 in osteoclasts and bone metabolism. By analysis of microCT and bone histomorphometry of 16-week-old male mice, we confirmed that the Baf155 deficient mice significantly increased the TRAP5b and CTX which are the representative serum markers of bone resorption, and thereby decreased the bone mineral density. By using human osteoclasts, we demonstrated that BAF155 expression during osteoclast differentiation stages. The BAF155 expression was significantly decreased in mature osteoclast, not bone marrow macrophage or osteoclast precursor stage, in contrast BAF170 expression was increased. Also, we found several target candidates from RNA sequencing analysis. We are investigating the validation of candidates by RT-PCR and immunoblotting.
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), 19K10044
• Study on mature bone formation and regeneration by Nuero-Skeletal regulations
  Grants-in-Aid for Scientific Research
  01 Apr. 2018 - 31 Mar. 2021
  IImura Tadahiro
  The lamellar structure of bone, which endows biomechanical rigidity to support the host organism, is observed in mammals, including humans. It is therefore essential to develop a quantitative analysis to evaluate the lamellarity of bone, which would especially be useful for the pharmacological evaluation of anti-osteoporotic drugs. This study applied a current system for the semi-automatic recognition of fluorescence signals to the analysis of un-decalcified bone sections from rat and monkey specimens treated with teriparatide (TPTD). Our analyses on bone formation pattern and collagen topology indicated that TPTD augmented bone lamellarity and bone collagen linearity, which were possibly associated with the recovery of collagen cross-linking, thus endowing bone rigidity.
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), 18H02983
• Analysis of new therapeutic target molecules for osteoporosis based on the chromatin information
  Grants-in-Aid for Scientific Research
  30 Jun. 2017 - 31 Mar. 2019
  Imai Yuuki; Yanagihara Yuta; Iimura Tadahiro; Saeki Noritaka; Lee Jiwon
  Zinc finger and SCAN domain containing 10 (Zscan10) was identified as a novel transcription factor that is involved in osteoclast differentiation in our previous report. However, the biological functions of Zscan10 are not fully understood. First, Zscan10 KO RAW264 (KO) cells were established by genome editing using CRISPR/Cas9 and single cell sorting. Zscan10 might regulate transcription of the genes that negatively control osteoclastogenesis. To understand gene expression profiles controlled by Zscan10, RNA-seq was performed and stringent analyses identified the haptoglobin gene (Hp) as a possible target of Zscan10. rHp treatment suppressed TRAP activity of KO cells without affecting cell viability. Furthermore, it has been reported that Hp KO mice exhibit decreased bone mass and increased osteoclast number. Taken together, this study suggests that Zscan10 negatively regulates osteoclast differentiation through transcription of Hp.
  Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Research (Exploratory), Ehime University, 17K19728
• Morphometrical and quantitative transcriptome analyses of C-C chemokine receptor 5 in functional structure of osteoclasts
  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
  01 Apr. 2016 - 31 Mar. 2019
  LEE JIWON; Iimura Tadahiro
  This study demonstrated that the blockade of CCR5 using its specific antibodies impaired in vitro human osteoclastogenesis with disorganized actin rings, but not osteoblastogenesis. Ccr5-deficient mice with dysfunctional osteoclasts were resistant to osteoporotic stimulation via the administration of receptor activator of nuclear factor kappa-B ligand (RANKL), which induces osteoporosis independently of the inflammatory and immunomodulatory responses. Furthermore, CCL5, a ligand for CCR5, enhanced the integrin- and chemokine-mediated pathways in osteoclast. The present study experimentally provides further evidence that CCR5 plays an essential role in bone destructive diseases through the functional regulation of osteoclasts, thus suggesting a skeletal benefit of the CCR5-targeting therapy.
  Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Ehime University, 16K20412
• Multimode analyses of skeletogenesis by imaging, simulation and omics
  Grants-in-Aid for Scientific Research
  01 Apr. 2014 - 31 Mar. 2018
  Iimura Tadahiro
  The purpose of this research grant was to identify important genes during skeletal development, and further validate the role of candidate genes by analysis of knock-out mice. We identified some cc-chemokines expressing in developing skeletal tissues. One of prominent advance in this research was that a chemokine receptor CCR5, also a HIV co-receptor, was essential for osteoporosis. Clinical reports suggested that HIV treatment targeting CCR5 may cause less-susceptibility to bone-destructive diseases such as rheumatoid arthritis and osteoporosis. We uncovered that anti-CCR5 neutralization antibody as well as a CCR5 inhibitory drug, Maraviroc, blocked osteoclast differentiation and function through damaging their actin-ring formation. Moreover, CCR5-deficient mice were resistant to osteoporotic stimuli. These findings experimentally supports the clinical reports as mentioned above, and suggest that HIV therapy targeting CCR5 may provide skeletal merits.
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Ehime University, 26293392
• Pathophysiological investigation of bone cell communications regulated by chemokine network
  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
  01 Apr. 2014 - 31 Mar. 2016
  Lee Ji-Won
  - Physiological roles of CCR5 in bone metabolism; Ccr5-deficient mice had significantly increased number and size of osteoclasts, although they did not show significant difference in BMD compared to their wild-type littermates. In keeping with osteoclast dysfuction, Ccr5-deficient mice were less susceptible to RANKL-induced bone loss, reflecting functional impairment of osteoclasts.
  - Elucidation of signaling pathway in Ccr5-/- mice; Ccr5-deficient osteoclasts showed decreased bone resorption activity accompanied with impaired and disorganized adhesive structures, demonstrated using confocal and super-resolution microscopy. Our molecular results suggested that CCR5-mediated signal was involved in integrin-mediated small GTPase activation that was required for proper osteoclasts function. Our findings unveil unique and essential roles of CCR5 in bone metabolism and bone destruction diseases, and have implications concerning bone physiopathology for the HIV therapy targeting CCR5.
  Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Ehime University, 26861549