Bone Research最新文献

{"title":"Integrated stress signaling pathways promote adaptive reprogramming for chondrocyte survival in Metaphyseal Chondrodysplasia Type Schmid.","authors":"Qing Yao, Wilson Cheuk Wing Chan, Yuliana Sandraling Lie, Cheng Wang, Vivian Chor Wing Ng, Zhijia Tan, Steven Lim Cho Pei, Ning Chen, Michael Kai Tsun To, Kathryn Song Eng Cheah, Danny Chan","doi":"10.1038/s41413-026-00587-5","DOIUrl":"10.1038/s41413-026-00587-5","url":null,"abstract":"<p><p>Collagen X, encoded by the Col10a1 gene, is expressed specifically by hypertrophic chondrocytes (HCs) in the cartilage. Mutations of the Col10a1 gene in humans, which increase the endoplasmic reticulum (ER) stress in HCs, lead to metaphyseal chondrodysplasia type Schmid (MCDS). However, the mechanism of how HCs respond to ER stress to affect bone development and growth is not entirely understood. In this study, we generated a new mouse model harboring a 13 bp deletion (13del) in the endogenous Col10a1 gene. These 13del-MCDS mice display all the known clinical characteristics of human MCDS, as well as the molecular and cellular changes within the growth plate cartilage. For the first time, we found that triggering ER stress leads to activation of hypoxia and HIFs pathways in vivo, promoting cellular survival in HCs of the 13del-MCDS mice. To test whether the activated hypoxia and HIFs pathways are triggered by ER stress or extrinsic factors, we generated WT/GFP-MCDS chimera mice. Our findings showed that the activation of hypoxia and the hypoxic pathway is an intrinsic response to ER stress, which may partly occur through activation of ATF4 in HCs of mice. In parallel, p53 pathway changes and autophagy-associated protein-quality-control responses were observed in spatial association with altered chondrocyte differentiation and survival. These findings reveal coordinated engagement of multiple stress-response pathways during the adaptive response of hypertrophic chondrocytes to chronic ER stress.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"15-PGDH inhibition in osteoarthritis: PGE₂ skeletal interoception, cartilage regeneration and compartment-managed disease modification.","authors":"Qiaojie Chen, Haijun Zhang, Yang Chen, Bo Zhang","doi":"10.1038/s41413-026-00589-3","DOIUrl":"10.1038/s41413-026-00589-3","url":null,"abstract":"<p><p>Osteoarthritis is a whole-joint disease in which cartilage loss, synovial inflammation, subchondral bone remodelling and pain-related neural changes co-evolve, yet structural improvement does not reliably translate into pain relief. This Review centres prostaglandin E₂ (PGE₂) skeletal interoception in the translational framework for 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibition. In skeletal interoception, PGE₂ produced in mechanically stressed bone and osteochondral tissues is sensed by prostaglandin E receptor 4 (EP4)-positive sensory afferents, relayed to central circuits and translated into altered sympathetic norepinephrine output. Because 15-PGDH catabolises PGE₂, its inhibition may prolong the persistence and spatial reach of this interoceptive cue while also acting locally on chondrocyte state. This combined local and interoceptive action offers a plausible mechanism for cartilage repair and pain modulation, but may also create compartment-specific risk when prolonged PGE₂ persists in synovium or subchondral bone. We compare 15-PGDH inhibition with upstream synthesis blockade and receptor-specific strategies, and propose that development should be organised around three checkpoints: cartilage-enriched exposure, durability under mechanical load and structure-pain coherence. Current evidence supports cautious development rather than broad generalisation; clinical translation will require compartment-resolved pharmacokinetics/pharmacodynamics, EP-receptor attribution and early surveillance for synovial, osteochondral and pain-system liabilities.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bi-allelic EPHA2 mutations cause dysosteosclerosis by inhibiting osteoclastogenesis and enhancing osteoblastogenesis.","authors":"Xi Chen, Xin Li, Zenghui Gu, Qi Lu, Xinyu Qian, Yier Fan, Ke Deng, Shanshan Li, Zhe Wei, Yang Xu, Wenzhen Fu, Hou-Feng Zheng, Weiwei Hu, Zhenlin Zhang","doi":"10.1038/s41413-026-00565-x","DOIUrl":"10.1038/s41413-026-00565-x","url":null,"abstract":"<p><p>Erythropoietin-producing hepatocellular (EPH) receptors, the largest receptor tyrosine kinase family, have been shown to play a crucial role in normal physiological processes and pathologies. EPHA2, encoded by EPHA2 gene, a member of the EPH receptor family, has been implicated in cataracts and various bone tumors, including osteosarcoma, chondrosarcoma, and bone metastases of breast cancer. However, no association between the EPHA2 gene and genetic skeletal disorders has been reported to date. Here, we identified a Chinese family with a diagnosis of dysosteosclerosis, presenting with significant increase in lumbar spine bone mineral density, multifocal sclerotic lesions throughout the body, sclerotic skull, platyspondyly and sandwich vertebrae, and demonstrated compound heterozygous mutations in EPHA2 gene (c.890 C > T, p.Thr297Met; c.988dupT, p.Ser330PhefsX51). We observed a reduction in numerous sclerotic lesions in patients during the five-year follow-up. To systematically investigate the molecular mechanisms of pathogenesis, we employed a range of methodologies, including in vitro cellular assays, genome-wide association studies analysis, induced pluripotent stem cells models and Epha2 knockout mice models. We have determined that loss-of-function mutations in EPHA2 gene lead to dysosteosclerosis through enhancing mesenchymal stem cells osteogenic differentiation and downregulating the p38-MAPK pathway, leading to decreased osteoclast differentiation. Consequently, we proposed and validated EPHA2 as a viable therapeutic target for osteoporosis by constructing femoral fracture mice models and ovariectomized mice models. In summary, this study identifies bi-allelic loss-of-function mutations in EPHA2 gene lead to dysosteosclerosis and its underlying mechanisms, and suggests EPHA2 as a potential therapeutic target for osteoporosis.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C-type lectin receptors: bone remodeling and therapeutic potential.","authors":"Marina Kleim, Aline Bozec, Manuel Weber, Bettina Groetsch","doi":"10.1038/s41413-026-00567-9","DOIUrl":"10.1038/s41413-026-00567-9","url":null,"abstract":"<p><p>Osteoimmunology explores the interplay between the skeletal system and the immune system. It focuses on the identification of shared signaling pathways and the mechanisms of mutual regulation. Bone homeostasis depends on the balance between the activity of bone-forming osteoblasts and bone-resorbing osteoclasts. Interestingly, the crosstalk between osteoclasts, osteoblasts, osteocytes, and immune cells not only shapes bone remodeling but also influences immune responses. A central pathway in osteoclast differentiation is the receptor activator of nuclear factor-κB ligand (RANKL) signaling, which induces NFATc1, the master transcription factor of osteoclastogenesis. Recent evidence shows that immunoreceptor tyrosine-based activation motif (ITAM)-containing co-receptors enhance RANKL-induced signaling, underscoring their essential role in osteoclast activation and differentiation. Increasing attention has been directed toward C-type lectin receptors (CLRs), such as Dectin-1, Mincle, and DC-SIGN. These receptors have historically been recognized for their functions in antifungal and antibacterial immunity. However, their expression on both immune cells and osteoclasts links CLR signaling to osteoclastogenesis, as CLR engagement signals through ITAM pathways, contributing to NFAT activation. Therefore, CLRs could function as co-receptors for RANKL in human osteoclast biology, although the underlying mechanisms remain poorly defined. This review synthesizes current knowledge on CLR signaling and its role in osteoclastogenesis. It examines how CLR-mediated pathways influence bone resorption and evaluates their therapeutic potential. Finally, the review discusses the challenges of translating these insights into clinical applications and highlights emerging strategies for targeting CLRs in bone-related pathologies.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13620164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomaterial-mediated blood clot formation: a key to unlocking osteogenic synergy for bone regeneration.","authors":"Dong Zhang, Laiqiang Tong, Lijie Mao, Dong Han, Fangping Chen, Changsheng Liu","doi":"10.1038/s41413-026-00559-9","DOIUrl":"10.1038/s41413-026-00559-9","url":null,"abstract":"<p><p>Bone hemorrhage presents serious clinical challenges due to its high morbidity and mortality. Autologous coagulation forms blood clots that both halt bleeding and provide a natural scaffold for bone repair. The dynamic formation and dissolution of blood clots maintain a delicate balance between hemostasis and regeneration. Clot architecture and cytokine composition play pivotal roles in directing bone repair. These insights inspire biomimetic strategies using engineered biomaterials to regulate clot behavior, a central theme in designing bone-replacement systems that integrate hemostasis with osteogenesis. This review highlights the processes of clot formation following bone trauma and the contribution of cytokine-mediated signaling to bone repair. Particular emphasis is placed on how biomaterial implants modulate clot function via their physicochemical properties, such as chemical composition, structural characteristics, hydrophilicity, and surface charge. Additionally, the review examines the role of the clots during the early stages of bone injury and discusses the rational design principles for materials aimed at optimizing coagulation control and osteogenesis. Overall, this review reframes the clot not as a passive by-product of trauma but as an interface through which biomaterials seamlessly merge hemostasis and osteogenesis, offering a roadmap for multifunctional bone-replacement systems that halt bleeding while programming robust bone repair.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omic analysis of jaw-bone periosteum identifies the role of macrophage-derived SPP1 in Ctsk+Fmod+ periosteal cells","authors":"Zumu Yi,Yeyu Liu,Jing Wang,Chen Deng,Yixin Jin,Yili Qu,Chen Hu,Yi Man","doi":"10.1038/s41413-026-00585-7","DOIUrl":"https://doi.org/10.1038/s41413-026-00585-7","url":null,"abstract":"Abstract Periosteal cells (PCs) play a crucial role in bone regeneration. Currently, the spatial landscapes of jaw-bone periosteum during bone grafting remains unclear. In this study, we propose a modified guided bone regeneration (GBR) model and integrate single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to dissect its spatial characteristics. We identify a functional subset of Ctsk + Fmod + PCs within the jaw-bone periosteum of rat and human. In addition, we describe a spatial niche around the bone graft substitute, characterized by massive infiltration of macrophages interacting with Ctsk + Fmod + PCs. Notably, SPP1 secreted by macrophages attenuates the osteogenic capacity of Ctsk + Fmod + PCs. The discovery of this Ctsk + Fmod + subcluster, characterized by osteoprogenitor features and close interactions with macrophages, sheds light on the composition of the subperiosteal microenvironment and the heterogeneity of jaw-bone PCs.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"1 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020650","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}

{"title":"Bone aging: a paradigm of multiscale degeneration and targeted rejuvenation.","authors":"Kangpeng Li, Chenyuan Gao, Ti Zhang, Cheng Wang, Xiao Geng, Xinguang Wang, Hua Tian","doi":"10.1038/s41413-026-00582-w","DOIUrl":"10.1038/s41413-026-00582-w","url":null,"abstract":"<p><p>Bone aging is not merely a process of bone mass loss but rather a multi-level, networked degenerative phenomenon spanning molecular, cellular, tissue, and system levels. With the accelerating pace of global population aging, bone degenerative diseases have emerged as a major public health challenge. Consequently, there is an urgent need to elucidate the underlying mechanisms from an integrated perspective and to develop innovative intervention strategies. This review systematically synthesizes the comprehensive landscape of bone aging. At the macroscopic level, bone aging is characterized by declines in bone mass, microstructure, and biomechanical properties, ultimately leading to increased fragility. At the microscopic level, its pathogenesis involves dysfunction across multiple layers. Molecular mechanisms include genetic and epigenetic alterations, oxidative stress, the senescence-associated secretory phenotype, and dysregulation of key signaling pathways. Cellular level changes involve telomere attrition, mitochondrial and endoplasmic reticulum dysfunction, impaired proteostasis, altered nutrient sensing, and cellular senescence. At the microenvironmental and systemic levels, contributing factors include chronic inflammation, hormonal changes, and extracellular matrix remodeling. Correspondingly, intervention strategies include non-pharmacological approaches, such as dietary optimization, physical activity, and avoidance of alcohol and tobacco, as well as pharmacological therapies, including antiresorptive agents, anabolic bone-forming drugs, and senolytics. Emerging therapeutic avenues include regenerative medicine, gene therapy, and tissue engineering. Future research should focus on constructing a multi-omics-integrated bone aging atlas, developing bone organoids and computational models, establishing multimodal risk assessment systems, advancing precision therapies that target aging-related pathways, and promoting prevention-centered public health strategies. This review aims to provide a systematic framework for understanding the complex pathophysiology of bone aging and to provide key insights and directions for future interdisciplinary collaborations, translational research, and clinical interventions.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13572547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148962947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WDR23 prevents bone loss by promoting autophagic degradation of TRAF6 in osteoclastogenesis.","authors":"Hye-Won Park, Jungeun Yu, Jiyeon Yu, Jinseon You, Yeon Hee Kook, Joo-Yong Lee, Taesoo Kim, Chul-Ho Lee, Hee-Chung Chung, Jong-Soon Choi, Sangkyu Lee, Jaerang Rho","doi":"10.1038/s41413-026-00560-2","DOIUrl":"10.1038/s41413-026-00560-2","url":null,"abstract":"<p><p>Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a pivotal adaptor molecule in the receptor activator of nuclear factor-κB (RANK) and its ligand (RANKL) signaling pathways, which are essential for osteoclastogenesis. In this study, we identified WD40 repeat-containing protein 23 (WDR23), also known as DDB1-CUL4 associated factor 11 (DCAF11), as a novel binding partner of TRAF6. Our findings demonstrate that WDR23/DCAF11 acts as a negative feedback regulator of RANK/RANKL-induced osteoclastogenesis by promoting the autophagy-dependent degradation of TRAF6. Notably, RANKL induced the upregulation of WDR23 expression during osteoclastogenesis. WDR23 physically interacted with the TRAF domain of TRAF6 via the WD40 repeat domains 1 and 2 of WDR23, resulting in reduced TRAF6 protein stability by its autophagy-dependent degradation during osteoclastogenesis. By modulating TRAF6 protein levels, WDR23 attenuated RANKL signaling cascades, including nuclear factor-κB and mitogen-activated protein kinases, thereby downregulating the expression of osteoclastogenic markers, such as nuclear factor of activated T-cell c1, tartrate-resistant acid phosphatase, dendritic cell-specific transmembrane protein, V-ATPase subunit d2 and cathepsin K. Conversely, WDR23 knockdown or deficiency enhanced RANKL-induced osteoclastogenesis by preventing the autophagy-dependent degradation of TRAF6. WDR23-deficient mice exhibit an osteoporotic bone phenotype characterized by elevated osteoclast formation and reduced bone mass. Collectively, these results establish WDR23 as a key negative feedback regulator of RANKL-induced osteoclastogenesis via autophagy-mediated TRAF6 degradation and underscore its potential as a therapeutic target for bone disorders associated with aberrant osteoclast formation and function.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13558766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spleen-derived circulating intercellular adhesion molecule 2 promotes osteosclerosis in chronic myelofibrosis","authors":"Sirion Aksornthong, Kerstin Tiedemann, Mélanie Welman, Alexandra Mazharian, Marie Lordkipanidzé, Yotis A. Senis, Svetlana V. Komarova","doi":"10.1038/s41413-026-00575-9","DOIUrl":"https://doi.org/10.1038/s41413-026-00575-9","url":null,"abstract":"Mutations in the gene coding G6b-B, <italic>Mpig6b</italic> in mice, and <italic>MPIG6B</italic> in humans lead to myelofibrosis, progressive splenomegaly and osteosclerosis. Aberrant megakaryocyte function in bone marrow and spleen may affect bone cells through cell-cell contact or soluble factors. We aimed to assess the role of circulating factors produced by splenic cells in mediating osteosclerosis in <italic>Mpig6b</italic>^{<italic>−/−</italic>} mice using splenectomy, a procedure commonly used in clinics. Splenectomy or sham surgery was performed on 32-week-old female <italic>Mpig6b</italic>^{<italic>−/−</italic>} and littermate wildtype (WT) mice, when splenomegaly and long bone osteosclerosis were established. Twenty weeks later, the hematopoietic parameters and bone structure of the femur and lumbar vertebra were analyzed. Splenectomy significantly improved platelet count, but the larger platelet size persisted in <italic>Mpig6b</italic>^{<italic>−/−</italic>}mice. The <italic>Mpig6b</italic>^{<italic>−/−</italic>} femurs with established osteosclerosis were not affected by splenectomy. In contrast, splenectomy prevented the development of osteosclerosis in vertebrae of <italic>Mpig6b</italic>^{<italic>−/−</italic>} mice. Significant vertebral bone loss and increased circulating TRACP 5b were demonstrated in splenectomized <italic>Mpig6b</italic>^{<italic>−/−</italic>} mice compared to sham-operated and WT mice. Using quantitative plasma proteomics, we identified intercellular adhesion molecule 2 (ICAM2) as significantly increased in <italic>Mpig6b</italic>^{<italic>−/−</italic>} mice compared to WT and reversed to normal levels after splenectomy. The interaction of membrane-bound ICAM2 and MAC1 was reported to be critical for osteoclast fusion. Our in vitro study revealed that soluble recombinant ICAM2 dose-dependently inhibited osteoclast fusion, suggesting that competitive binding of MAC1 with soluble ICAM2 prevented its interaction with membrane-bound ICAM2. Thus, we identified the soluble ICAM2 as a novel inhibitor of osteoclast fusion and mediator of osteosclerosis in <italic>Mpig6b</italic>^{<italic>−/−</italic>} mice.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"392 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003668","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}

{"title":"Fibroblast growth factor receptor signaling in maturing osteoblasts controls cell-matrix interactions critical for osteocyte survival","authors":"Debabrata Patra, Craig Smith, Chenming Wei, Courtney M. Mazur, Ilemona Ameadaji, Tiandao Li, Marc N. Wein, Matthew J. Silva, David M. Ornitz","doi":"10.1038/s41413-026-00583-9","DOIUrl":"https://doi.org/10.1038/s41413-026-00583-9","url":null,"abstract":"The terminal differentiation of osteoblasts into osteocytes, the most abundant cell type in cortical bone, is critical for skeletal homeostasis. Osteocyte loss is a hallmark of bone aging and fragility, yet the mechanisms regulating osteocyte formation and survival are poorly understood. We show that inactivation of fibroblast growth factor receptor 1 (Fgfr1) in the mature osteoblast lineage results in extensive osteocyte death, identifying FGFR1 signaling as essential for osteocyte viability and bone integrity. Lineage tracing and analysis of endogenous and induced appositional bone formation revealed that newly embedded osteocytes fail to survive without FGFR1. These osteocytes exhibited ectopic expression of osteocalcin and podoplanin within sclerostin-positive, TUNEL-reactive lacunae, along with defective dendrite formation and disruption of the local lacunocanalicular network. RNA sequencing of cortical bone demonstrated reduced expression of extracellular matrix (ECM) genes and neuronal regulatory genes, while histological and ultrastructural analyses showed disorganized collagen fibrils, diminished osteoid, and abnormal mineralization. In vitro, FGF signaling in Ocy454 cells regulated gene programs involved in development, axon guidance, and bone ECM organization, highlighting a dual function for FGF signaling in which it controls both matrix-dependent and intrinsic cell differentiation mechanisms during the osteoblast-to-osteocyte transition. We propose that FGFR1 deficiency causes ECM disorganization and impaired dendrite formation, disrupting osteocyte communication with neighboring bone and vascular cells, ultimately leading to cell death. These findings establish FGFR signaling as a critical regulator of osteocyte differentiation, viability of bone-embedded osteocytes, and bone homeostasis.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"494 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899561","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}