Bone Research最新文献

Advancing osteoarthritis research: the role of AI in clinical, imaging and omics fields 推进骨关节炎研究：人工智能在临床、成像和海洋学领域的作用

IF 12.7 1区医学

Bone Research Pub Date : 2025-04-22 DOI: 10.1038/s41413-025-00423-2

Jingfeng Ou, Jin Zhang, Momen Alswadeh, Zhenglin Zhu, Jijun Tang, Hongxun Sang, Ke Lu

{"title":"Advancing osteoarthritis research: the role of AI in clinical, imaging and omics fields","authors":"Jingfeng Ou, Jin Zhang, Momen Alswadeh, Zhenglin Zhu, Jijun Tang, Hongxun Sang, Ke Lu","doi":"10.1038/s41413-025-00423-2","DOIUrl":"https://doi.org/10.1038/s41413-025-00423-2","url":null,"abstract":"Osteoarthritis (OA) is a degenerative joint disease with significant clinical and societal impact. Traditional diagnostic methods, including subjective clinical assessments and imaging techniques such as X-rays and MRIs, are often limited in their ability to detect early-stage OA or capture subtle joint changes. These limitations result in delayed diagnoses and inconsistent outcomes. Additionally, the analysis of omics data is challenged by the complexity and high dimensionality of biological datasets, making it difficult to identify key molecular mechanisms and biomarkers. Recent advancements in artificial intelligence (AI) offer transformative potential to address these challenges. This review systematically explores the integration of AI into OA research, focusing on applications such as AI-driven early screening and risk prediction from electronic health records (EHR), automated grading and morphological analysis of imaging data, and biomarker discovery through multi-omics integration. By consolidating progress across clinical, imaging, and omics domains, this review provides a comprehensive perspective on how AI is reshaping OA research. The findings have the potential to drive innovations in personalized medicine and targeted interventions, addressing longstanding challenges in OA diagnosis and management.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"6 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SPI1 activates mitochondrial unfolded response signaling to inhibit chondrocyte senescence and relieves osteoarthritis SPI1激活线粒体未折叠反应信号，抑制软骨细胞衰老，缓解骨关节炎

IF 12.7 1区医学

Bone Research Pub Date : 2025-04-14 DOI: 10.1038/s41413-025-00421-4

Xiangyu Zu, Shenghong Chen, Zhengyuan Li, Lin Hao, Wenhan Fu, Hui Zhang, Zongsheng Yin, Yin Wang, Jun Wang

{"title":"SPI1 activates mitochondrial unfolded response signaling to inhibit chondrocyte senescence and relieves osteoarthritis","authors":"Xiangyu Zu, Shenghong Chen, Zhengyuan Li, Lin Hao, Wenhan Fu, Hui Zhang, Zongsheng Yin, Yin Wang, Jun Wang","doi":"10.1038/s41413-025-00421-4","DOIUrl":"https://doi.org/10.1038/s41413-025-00421-4","url":null,"abstract":"Chondrocyte senescence is a critical pathological hallmark of osteoarthritis (OA). Aberrant mechanical stress is considered a pivotal determinant in chondrocyte aging; however, the precise underlying mechanism remains elusive. Our findings demonstrate that SPI1 plays a significant role in counteracting chondrocyte senescence and inhibiting OA progression. SPI1 binds to the PERK promoter, thereby promoting its transcriptional activity. Importantly, PERK, rather than GCN2, facilitates eIF2α phosphorylation, activating the mitochondrial unfolded protein response (UPRmt) and impeding chondrocyte senescence. Deficiency of SPI1 in mechanical overload-induced mice leads to diminished UPRmt activation and accelerated OA progression. Intra-articular injection of adenovirus vectors overexpressing SPI1 and PERK effectively mitigates cartilage degeneration. In summary, our study elucidates the crucial regulatory role of SPI1 in the pathogenesis of chondrocyte senescence by activating UPRmt signaling through PERK, which may present a novel therapeutic target for treating OA.<figure>SPI1 alleviates the progression of OA by inhibiting mechanical stress-induced chondrocyte senescence through mitochondrial UPR signaling.</figure>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"40 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

NELL2, a novel osteoinductive factor, regulates osteoblast differentiation and bone homeostasis through fibronectin 1/integrin-mediated FAK/AKT signaling NELL2是一种新型的骨诱导因子，通过纤维连接蛋白1/整合素介导的FAK/AKT信号传导调节成骨细胞分化和骨稳态

IF 12.7 1区医学

Bone Research Pub Date : 2025-04-11 DOI: 10.1038/s41413-025-00420-5

Hairui Yuan, Xinyu Wang, Shuanglin Du, Mengyue Li, Endong Zhu, Jie Zhou, Yuan Dong, Shuang Wang, Liying Shan, Qian Liu, Baoli Wang

{"title":"NELL2, a novel osteoinductive factor, regulates osteoblast differentiation and bone homeostasis through fibronectin 1/integrin-mediated FAK/AKT signaling","authors":"Hairui Yuan, Xinyu Wang, Shuanglin Du, Mengyue Li, Endong Zhu, Jie Zhou, Yuan Dong, Shuang Wang, Liying Shan, Qian Liu, Baoli Wang","doi":"10.1038/s41413-025-00420-5","DOIUrl":"https://doi.org/10.1038/s41413-025-00420-5","url":null,"abstract":"Neural EGFL-like 2 (NELL2) is a secreted protein known for its regulatory functions in the nervous and reproductive systems, yet its role in bone biology remains unexplored. In this study, we observed that NELL2 was diminished in the bone of aged and ovariectomized (OVX) mice, as well as in the serum of osteopenia and osteoporosis patients. In vitro loss-of-function and gain-of-function studies revealed that NELL2 facilitated osteoblast differentiation and impeded adipocyte differentiation from stromal progenitor cells. In vivo studies further demonstrated that the deletion of NELL2 in preosteoblasts resulted in decreased cancellous bone mass in mice. Mechanistically, NELL2 interacted with the FNI-type domain located at the C-terminus of Fibronectin 1 (Fn1). Moreover, we found that NELL2 activated the focal adhesion kinase (FAK)/AKT signaling pathway through Fn1/integrin β1 (ITGB1), leading to the promotion of osteogenesis and the inhibition of adipogenesis. Notably, administration of NELL2-AAV was found to ameliorate bone loss in OVX mice. These findings underscore the significant role of NELL2 in osteoblast differentiation and bone homeostasis, suggesting its potential as a therapeutic target for managing osteoporosis.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"16 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cell communication and relevant signaling pathways in osteogenesis–angiogenesis coupling 骨生成-血管生成耦合中的细胞通讯及相关信号通路

IF 12.7 1区医学

Bone Research Pub Date : 2025-04-07 DOI: 10.1038/s41413-025-00417-0

Shuqing Li, Xinjia Cai, Jiahe Guo, Xiaolu Li, Wen Li, Yan Liu, Mengchun Qi

{"title":"Cell communication and relevant signaling pathways in osteogenesis–angiogenesis coupling","authors":"Shuqing Li, Xinjia Cai, Jiahe Guo, Xiaolu Li, Wen Li, Yan Liu, Mengchun Qi","doi":"10.1038/s41413-025-00417-0","DOIUrl":"https://doi.org/10.1038/s41413-025-00417-0","url":null,"abstract":"Osteogenesis is the process of bone formation mediated by the osteoblasts, participating in various bone-related physiological processes including bone development, bone homeostasis and fracture healing. It exhibits temporal and spatial interconnectivity with angiogenesis, constructed by multiple forms of cell communication occurring between bone and vascular endothelial cells. Molecular regulation among different cell types is crucial for coordinating osteogenesis and angiogenesis to facilitate bone remodeling, fracture healing, and other bone-related processes. The transmission of signaling molecules and the activation of their corresponding signal pathways are indispensable for various forms of cell communication. This communication acts as a “bridge” in coupling osteogenesis to angiogenesis. This article reviews the modes and processes of cell communication in osteogenesis-angiogenesis coupling over the past decade, mainly focusing on interactions among bone-related cells and vascular endothelial cells to provide insights into the mechanism of cell communication of osteogenesis-angiogenesis coupling in different bone-related contexts. Moreover, clinical relevance and applications are also introduced in this review.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"38 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143790156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Porcupine inhibition is a promising pharmacological treatment for severe sclerosteosis pathologies 豪猪抑制是一种有前途的药物治疗严重的硬化症病理

IF 12.7 1区医学

Bone Research Pub Date : 2025-04-07 DOI: 10.1038/s41413-025-00406-3

Timothy J. Dreyer, Jacob A. C. Keen, Leah M. Wells, Mark Hopkinson, Isabel R. Orriss, Gill Holdsworth, Andrew A. Pitsillides, Scott J. Roberts

{"title":"Porcupine inhibition is a promising pharmacological treatment for severe sclerosteosis pathologies","authors":"Timothy J. Dreyer, Jacob A. C. Keen, Leah M. Wells, Mark Hopkinson, Isabel R. Orriss, Gill Holdsworth, Andrew A. Pitsillides, Scott J. Roberts","doi":"10.1038/s41413-025-00406-3","DOIUrl":"https://doi.org/10.1038/s41413-025-00406-3","url":null,"abstract":"Sclerosteosis, an ultra-rare disorder characterised by high bone mass (HBM) and skeletal overgrowth, leads to facial paralysis, hearing loss and raised intracranial pressure, which is currently managed only through high-risk surgery. Sclerosteosis is caused by SOST mutations and loss of functional sclerostin, a protein that suppresses osteogenesis by antagonising Wnt/β-catenin signalling. Herein, using in vitro and in vivo approaches, we explore whether LGK974, another potent Wnt inhibitor that targets porcupine (PORCN, Wnt-specific acyltransferase), is a promising sclerosteosis therapeutic. In vitro assays showed that 100 nmol/L LGK974 significantly reduced osteoblast alkaline phosphatase (ALP) activity/mineralisation, decreased Wnt/osteoblast marker (Axin2, Runx2 and Ocn) expression, and downregulated ossification and the Wnt signalling pathway, without affecting osteoclast numbers/resorption. To assess in vivo effects, 6-week-old male and female Sost deficient (Sost-/-) mice received LGK974 for 4 weeks and right hindlimbs were subjected to 20 N peak loading to assess mechanoadaptive interactions. µCT revealed significant reductions in vertebral trabecular number and lower cortical bone volume in loaded and non-loaded tibiae in male and female LGK974-treated Sost-/- mice. Interestingly, the target engagement biomarker Axin2 was only significantly reduced in male vertebrae, which may indicate differences in male and female response to LGK974. This study also shows that PORCN inhibition may effectively limit characteristic HBM and skeletal overgrowth in sclerosteosis patients at sites with severe pathology.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"217 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143790159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

KIAA1199 (CEMIP) regulates adipogenesis and whole-body energy metabolism KIAA1199 （CEMIP）调节脂肪生成和全身能量代谢

IF 12.7 1区医学

Bone Research Pub Date : 2025-04-02 DOI: 10.1038/s41413-025-00415-2

Li Chen, Kaikai Shi, Nicholas Ditzel, Weimin Qiu, Michaela Tencerova, Louise Himmelstrup Dreyer Nielsen, Florence Figeac, Alexander Rauch, Yuhang Liu, Jiuyuan Tao, Veronika Sramkova, Lenka Rossmeislova, Greet Kerckhofs, Tatjana N. Parac-Vogt, Sébastien de Bournonville, Thomas Levin Andersen, Mikael Rydén, Moustapha Kassem

{"title":"KIAA1199 (CEMIP) regulates adipogenesis and whole-body energy metabolism","authors":"Li Chen, Kaikai Shi, Nicholas Ditzel, Weimin Qiu, Michaela Tencerova, Louise Himmelstrup Dreyer Nielsen, Florence Figeac, Alexander Rauch, Yuhang Liu, Jiuyuan Tao, Veronika Sramkova, Lenka Rossmeislova, Greet Kerckhofs, Tatjana N. Parac-Vogt, Sébastien de Bournonville, Thomas Levin Andersen, Mikael Rydén, Moustapha Kassem","doi":"10.1038/s41413-025-00415-2","DOIUrl":"https://doi.org/10.1038/s41413-025-00415-2","url":null,"abstract":"An increasing number of studies have characterized the bone as an endocrine organ, and that bone secreted factors may not only regulate local bone remodeling, but also other tissues and whole-body metabolic functions. The precise nature of these regulatory factors and their roles at bridging the bone, bone marrow adipose tissue, extramedullary body fat and whole-body energy homeostasis are being explored. In this study, we report that KIAA1199, a secreted factor produced from bone and bone marrow, previously described as an inhibitor of bone formation, also plays a role at promoting adipogenesis. KIAA1199-deficient mice exhibit reduced bone marrow adipose tissue, subcutaneous and visceral fat tissue mass, blood cholesterol, triglycerides, free fatty acids and glycerol, as well as improved insulin sensitivity in skeletal muscle, liver and fat. Moreover, these mice are protected from the detrimental effects of high-fat diet feeding, with decreased obesity, lower blood glucose and glucose tolerance, as well as decreased adipose tissue inflammation, insulin resistance and hepatic steatosis. In human studies, plasma levels of KIAA1199 or its expression levels in adipose tissue are positively correlated with insulin resistance and blood levels of cholesterol, triglycerides, free fatty acids, glycerol, fasting glucose and HOMA-IR. Mechanistically, KIAA1199 mediates its effects on adipogenesis through modulating osteopontin-integrin and AKT / ERK signaling. These findings provide evidence for the role of bone secreted factors on coupling bone, fat and whole-body energy homeostasis.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"104 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

M2 macrophages-derived exosomes for osteonecrosis of femoral head treatment: modulating neutrophil extracellular traps formation and endothelial phenotype transition M2巨噬细胞衍生外泌体治疗股骨头坏死：调节中性粒细胞胞外陷阱形成和内皮表型转变

IF 12.7 1区医学

Bone Research Pub Date : 2025-04-01 DOI: 10.1038/s41413-025-00412-5

Guanzhi Liu, Ruomu Cao, Qimeng Liu, Heng Li, Peng Yan, Kunzheng Wang, Run Tian, Pei Yang

{"title":"M2 macrophages-derived exosomes for osteonecrosis of femoral head treatment: modulating neutrophil extracellular traps formation and endothelial phenotype transition","authors":"Guanzhi Liu, Ruomu Cao, Qimeng Liu, Heng Li, Peng Yan, Kunzheng Wang, Run Tian, Pei Yang","doi":"10.1038/s41413-025-00412-5","DOIUrl":"https://doi.org/10.1038/s41413-025-00412-5","url":null,"abstract":"Exosomes have shown good potential in ischemic injury disease treatments. However, evidence about their effect and molecular mechanisms in osteonecrosis of femoral head (ONFH) treatment is still limited. Here, we revealed the cell biology characters of ONFH osteonecrosis area bone tissue in single cell scale and thus identified a novel ONFH treatment approach based on M2 macrophages-derived exosomes (M2-Exos). We further show that M2-Exos are highly effective in the treatment of ONFH by modulating the phenotypes communication between neutrophil and endothelium including neutrophil extracellular traps formation and endothelial phenotype transition. Additionally, we identified that M2-Exos’ therapeutic effect is attributed to the high content of miR-93-5p and constructed miR-93-5p overexpression model in vitro and in vivo based on lentivirus and adeno-associated virus respectively. Then we found miR-93-5p can not only reduce neutrophil extracellular traps formation but also improve angiogenic ability of endothelial cells. These results provided a new theoretical basis for the clinical application of ONFH therapeutic exosomes.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"33 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Callus organoids reveal distinct cartilage to bone transition mechanisms across donors and a role for biological sex 骨痂类器官揭示了不同供体间软骨到骨的转变机制和生物性别的作用

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-26 DOI: 10.1038/s41413-025-00418-z

Isaak Decoene, Hanna Svitina, Mohamed Belal Hamed, Anastassios Economou, Steve Stegen, Frank P. Luyten, Ioannis Papantoniou

{"title":"Callus organoids reveal distinct cartilage to bone transition mechanisms across donors and a role for biological sex","authors":"Isaak Decoene, Hanna Svitina, Mohamed Belal Hamed, Anastassios Economou, Steve Stegen, Frank P. Luyten, Ioannis Papantoniou","doi":"10.1038/s41413-025-00418-z","DOIUrl":"https://doi.org/10.1038/s41413-025-00418-z","url":null,"abstract":"Clinical translation of tissue-engineered advanced therapeutic medicinal products is hindered by a lack of patient-dependent and independent in-process biological quality controls that are reflective of in vivo outcomes. Recent insights into the mechanism of native bone repair highlight a robust path dependence. Organoid-based bottom-up developmental engineering mimics this path-dependence to design personalized living implants scaffold-free, with in-build outcome predictability. Yet, adequate (noninvasive) quality metrics of engineered tissues are lacking. Moreover, insufficient insight into the role of donor variability and biological sex as influencing factors for the mechanism toward bone repair hinders the implementation of such protocols for personalized bone implants. Here, male and female bone-forming organoids were compared to non-bone-forming organoids regarding their extracellular matrix composition, transcriptome, and secreted proteome signatures to directly link in vivo outcomes to quality metrics. As a result, donor variability in bone-forming callus organoids pointed towards two distinct pathways to bone, through either a hypertrophic cartilage or a fibrocartilaginous template. The followed pathway was determined early, as a biological sex-dependent activation of distinct progenitor populations. Independent of donor or biological sex, a cartilage-to-bone transition was driven by a common panel of secreted factors that played a role in extracellular matrix remodeling, mineralization, and attraction of vasculature. Hence, the secreted proteome is a source of noninvasive biomarkers that report on biological potency and could be the missing link toward data-driven decision-making in organoid-based bone tissue engineering.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"57 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tm4sf19 inhibition ameliorates inflammation and bone destruction in collagen-induced arthritis by suppressing TLR4-mediated inflammatory signaling and abnormal osteoclast activation Tm4sf19抑制通过抑制tlr4介导的炎症信号和破骨细胞异常活化，改善胶原诱导关节炎的炎症和骨破坏

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-24 DOI: 10.1038/s41413-025-00419-y

Sujin Park, Kwiyeom Yoon, Eunji Hong, Min Woo Kim, Min Gi Kang, Seiya Mizuno, Hye Jin Kim, Min-Jung Lee, Hee Jae Choi, Jin Sun Heo, Jin Beom Bae, Haein An, Naim Park, Hyeyeon Park, Pyunggang Kim, Minjung Son, Kyoungwha Pang, Je Yeun Park, Satoru Takahashi, Yong Jung Kwon, Dong-Woo Kang, Seong-Jin Kim

{"title":"Tm4sf19 inhibition ameliorates inflammation and bone destruction in collagen-induced arthritis by suppressing TLR4-mediated inflammatory signaling and abnormal osteoclast activation","authors":"Sujin Park, Kwiyeom Yoon, Eunji Hong, Min Woo Kim, Min Gi Kang, Seiya Mizuno, Hye Jin Kim, Min-Jung Lee, Hee Jae Choi, Jin Sun Heo, Jin Beom Bae, Haein An, Naim Park, Hyeyeon Park, Pyunggang Kim, Minjung Son, Kyoungwha Pang, Je Yeun Park, Satoru Takahashi, Yong Jung Kwon, Dong-Woo Kang, Seong-Jin Kim","doi":"10.1038/s41413-025-00419-y","DOIUrl":"https://doi.org/10.1038/s41413-025-00419-y","url":null,"abstract":"Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and abnormal osteoclast activation, leading to bone destruction. We previously demonstrated that the large extracellular loop (LEL) of Tm4sf19 is important for its function in osteoclast differentiation, and LEL-Fc, a competitive inhibitor of Tm4sf19, effectively suppresses osteoclast multinucleation and prevent bone loss associated with osteoporosis. This study aimed to investigate the role of Tm4sf19 in RA, an inflammatory and abnormal osteoclast disease, using a mouse model of collagen-induced arthritis (CIA). Tm4sf19 expression was observed in macrophages and osteoclasts within the inflamed synovium, and Tm4sf19 expression was increased together with inflammatory genes in the joint bones of CIA-induced mice compared with the sham control group. Inhibition of Tm4sf19 by LEL-Fc demonstrated both preventive and therapeutic effects in a CIA mouse model, reducing the CIA score, swelling, inflammation, cartilage damage, and bone damage. Knockout of Tm4sf19 gene or inhibition of Tm4sf19 activity by LEL-Fc suppressed LPS/IFN-γ-induced TLR4-mediated inflammatory signaling in macrophages. LEL-Fc disrupted not only the interaction between Tm4sf19 and TLR4/MD2, but also the interaction between TLR4 and MD2. μCT analysis showed that LEL-Fc treatment significantly reduced joint bone destruction and bone loss caused by hyperactivated osteoclasts in CIA mice. Taken together, these findings suggest that LEL-Fc may be a potential treatment for RA and RA-induced osteoporosis by simultaneously targeting joint inflammation and bone destruction caused by abnormal osteoclast activation.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"26 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143678082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bone marrow adipogenic lineage precursors are the major regulator of bone resorption in adult mice 骨髓成脂谱系前体是成年小鼠骨吸收的主要调节因子

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-19 DOI: 10.1038/s41413-025-00405-4

Jiawei Lu, Qi He, Huan Wang, Lutian Yao, Michael Duffy, Hanli Guo, Corben Braun, Yilu Zhou, Qiushi Liang, Yuewei Lin, Shovik Bandyopadhyay, Kai Tan, Yongwen Choi, X. Sherry Liu, Ling Qin

{"title":"Bone marrow adipogenic lineage precursors are the major regulator of bone resorption in adult mice","authors":"Jiawei Lu, Qi He, Huan Wang, Lutian Yao, Michael Duffy, Hanli Guo, Corben Braun, Yilu Zhou, Qiushi Liang, Yuewei Lin, Shovik Bandyopadhyay, Kai Tan, Yongwen Choi, X. Sherry Liu, Ling Qin","doi":"10.1038/s41413-025-00405-4","DOIUrl":"https://doi.org/10.1038/s41413-025-00405-4","url":null,"abstract":"Bone resorption by osteoclasts is a critical step in bone remodeling, a process important for maintaining bone homeostasis and repairing injured bone. We previously identified a bone marrow mesenchymal subpopulation, marrow adipogenic lineage precursors (MALPs), and showed that its production of RANKL stimulates bone resorption in young mice using Adipoq-Cre. To exclude developmental defects and to investigate the role of MALPs-derived RANKL in adult bone, we generated inducible reporter mice (Adipoq-CreER Tomato) and RANKL deficient mice (Adipoq-CreER RANKLflox/flox, iCKO). Single cell-RNA sequencing data analysis and lineage tracing revealed that Adipoq+ cells contain not only MALPs but also some mesenchymal progenitors capable of osteogenic differentiation. In situ hybridization showed that RANKL mRNA is only detected in MALPs, but not in osteogenic cells. RANKL deficiency in MALPs induced at 3 months of age rapidly increased trabecular bone mass in long bones as well as vertebrae due to diminished bone resorption but had no effect on the cortical bone. Ovariectomy (OVX) induced trabecular bone loss at both sites. RANKL depletion either before OVX or at 6 weeks post OVX protected and restored trabecular bone mass. Furthermore, bone healing after drill-hole injury was delayed in iCKO mice. Together, our findings demonstrate that MALPs play a dominant role in controlling trabecular bone resorption and that RANKL from MALPs is essential for trabecular bone turnover in adult bone homeostasis, postmenopausal bone loss, and injury repair.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"183 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0