Bone Research最新文献

{"title":"Spatially resolved osteoblast-traced transcriptomics uncovers TGF-β as a combination target with sclerostin in osteoporosis","authors":"Ahyoun Choi, Ji Yeon Lee, Hyejin Yoon, Xiangguo Che, Minkyeong Choi, Yongkuk Park, Kyoungseob Shin, Hyunho Lee, Jimin Park, Sung Hye Kong, Jinhyun Kim, Amos Chungwon Lee, Chan Soo Shin, Je-Yong Choi, Jungwoo Lee, Sunghoon Kwon, Sang Wan Kim","doi":"10.1038/s41413-026-00521-9","DOIUrl":"https://doi.org/10.1038/s41413-026-00521-9","url":null,"abstract":"Dynamic transitions of mature osteoblasts between active and quiescent states are essential for bone homeostasis and present a promising target for osteoanabolic therapy. However, these transitions remain poorly understood due to cellular heterogeneity and limited spatial context. Here, we employed spatially resolved osteoblast-traced transcriptomics, integrating an osteoblast-specific lineage tracing study and spatially resolved laser-activated cell sorting (SLACS), to profile osteoblast states on quiescent bone surfaces. This approach identified transforming growth factor-beta (TGF-β) signaling as a regulator of osteoblast activation. We further validated this role using single-cell RNA sequencing, in vitro functional assays, and in vivo. In a hindlimb unloading mouse model, dual inhibition of TGF-β and sclerostin enhanced bone mass and mitigated bone loss more effectively than sclerostin inhibition alone. These findings reveal a mechanistic role for TGF-β in regulating osteoblast dynamics and propose a dual-target therapeutic strategy that enhances the efficacy of anti-sclerostin treatment in osteoporosis.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"263 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147585911","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":"Genetic study identifies novel genes in developmental dysplasia of the hip.","authors":"Soichiro Yoshino,Shibo Chen,Ryosuke Yamaguchi,Taishi Kurakazu,Konstantinos Hatzikotoulas,Yoshinao Koike,Daisuke Inoue,Yusuke Kohno,Kan Sasaki,Hyonmin Choe,Shoji Baba,Toshihiko Hara,Juji Ito,Yaichiro Okuzu,Kyohei Shiomoto,Tomoyuki Nakamura,Gaku Koyano,Tomohiro Shimizu,Koichi Kinoshita,Eiji Takahashi,Takeshi Utsunomiya,Daisuke Hara,Taishi Sato,Shinya Kawahara,Ayumi Kaneuji,Takuaki Yamamoto,Daisuke Takahashi,Tetsuya Jinno,Tsutomu Kawano,Koji Goto,Michiaki Takagi,Taro Mawatari,Yutaka Inaba,Tetsuro Nakamura,Tamon Kabata,Satoshi Hamai,Goro Motomura,Lorraine Southam,J Mark Wilkinson,Eleftheria Zeggini,Shiro Ikegawa,Yasuharu Nakashima,Chikashi Terao","doi":"10.1038/s41413-026-00514-8","DOIUrl":"https://doi.org/10.1038/s41413-026-00514-8","url":null,"abstract":"Developmental dysplasia of the hip (DDH), a morphological abnormality of the hip joint, is a well-recognized risk factor for hip osteoarthritis (OA). Much remains unknown about the genetic factors of DDH and its subtypes. To further understand its genetic basis, we conducted genome-wide association studies (GWASs) using a total of 1 085 Japanese DDH cases (including 788 hip dysplasia cases without dislocation and 297 cases with dislocated hip) and 24 000 controls. Additionally, we meta-analyzed with United Kingdom (UK) DDH GWAS and the largest hip OA GWAS to date. We identified three genome-wide significant novel loci, COL11A2, CALN1 and TRPM7, associated with hip dysplasia without dislocation. None of these signals were significant in dislocated hips, and additionally two of the signals had an opposite direction of association, suggesting distinct genetic architectures between the subtypes. The Japanese DDH GWAS identified five associated loci (VEGF-C, FOXC1, SMC2, SLC38A4, and TRPM7), and the trans-ancestry meta-analysis with UK revealed two loci (COL11A1 and GDF5) supported by strong trans-ancestry genetic correlation (r = 1.0). In total, nine loci were identified for DDH and its subtypes, with hip dysplasia without dislocation showing distinct genetic signals from hip dislocation. The meta-analysis of DDH and hip OA identified five novel signals for hip OA. Susceptibility loci and heritability enrichment analyses implicated pathways involving bone formation, collagen type XI trimer, and chondrocyte development, as well as their gene regulation, in DDH. These findings enhance understanding of the genetic architecture and biological pathways underlying DDH, providing new insights into its relationship with OA.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"50 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147578111","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":"Spectrum and functions of ion channels and transporters in osteoclasts.","authors":"Hongyu Chen,Yanli Zhang,Yulong Zhu,Xiang Xiao,Shanshan Huang,Xiaohong Duan","doi":"10.1038/s41413-026-00513-9","DOIUrl":"https://doi.org/10.1038/s41413-026-00513-9","url":null,"abstract":"Osteoclasts are essential for bone resorption and interact with osteoblasts during bone remodeling. Ion channels and transporters located in the ruffled border or intracellular vesicles coordinate the transport of various ions and substrates, which is fundamental to the primary functions of osteoclasts. Numerous channels and transporters are implicated in bone metabolic disorders and genetic diseases. Among these, the voltage-gated chloride channel 7 (ClC-7) and vacuolar proton ATPases (V-ATPase) represent the most well-characterized examples in osteoclasts. Using the classification system of the Transporter Classification Database, we reviewed nearly 90 osteoclastic ion channels and transporters, categorizing them into six groups: ATPases, cation channels, anion channels, complex transporters, organic substance transporters, and ATP-binding cassette transporters. We summarized recent advances in their subcellular localization, transported substrates, associated diseases, and physiological roles in relevant biological functions and signaling pathways. Notably, transporters for hydrogen, chloride, phosphate, and calcium are particularly critical for osteoclast function. We also reviewed therapeutic candidates targeting these ion channels and discussed strategies for their future development. As transcriptome and other advanced techniques have identified more channels and transporters in osteoclasts, the diversity and unexplored functions of these molecules may exceed previous understanding. Increased attention to their widespread distributions and interactions could reveal new therapeutic targets for osteoclast-related and other bone disorders.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"23 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147524661","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":"Identification of Smmhc-expressing mesenchymal cells in orofacial bone at single-cell resolution.","authors":"Yi Fan,Yali Wei,Zhuoxuan Wu,Qin Huang,Chen Cui,Zucen Li,Ruoshi Xu,Quan Yuan,Chenchen Zhou","doi":"10.1038/s41413-026-00518-4","DOIUrl":"https://doi.org/10.1038/s41413-026-00518-4","url":null,"abstract":"Craniofacial bone regeneration remains a major clinical challenge, yet the identity of orofacial mesenchymal stem/stromal cells (OMSCs) has not been fully elucidated. Here, we performed single-cell RNA sequencing (scRNA-seq) on mouse orofacial bone and identified multiple stromal cell clusters. Cell-cell communication mapping and trajectory inference uncovered the heterogeneity of OMSCs and functional divergence among subpopulations. We identified a previously unrecognized population, Smmhc-expressing mesenchymal stem/stromal cells (MSCs), at the earliest stage of the progenitor lineage trajectory. In vivo lineage tracing demonstrated that Smmhc+ MSCs are multipotent, giving rise to osteoblasts, osteocytes, periodontal ligament (PDL) cells, and dental pulp cells. Targeted ablation of Smmhc+ MSCs using SmmhcCreER;iDTR mouse model led to impaired orofacial bone development and disrupted orofacial tissue homeostasis, characterized by reduced osteogenic differentiation and non-cell autonomous reduction of bone resorption. Collectively, this study establishes a cellular atlas of OMSCs and identifies Smmhc+ MSCs as a functionally indispensable subset for craniofacial bone homeostasis, orchestrating the dynamic balance between osteogenesis and bone resorption within the orofacial skeletal niche.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"92 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147495215","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":"Expansion of bone marrow adipocytes in obese mice leads to PD-L1-driven bone marrow immunosuppression and osteoclastogenesis.","authors":"Samantha N Costa,Carolyn Chlebek,Lindsey Gray,Peter Caradonna,Sergey Ryzhov,Clifford J Rosen","doi":"10.1038/s41413-026-00509-5","DOIUrl":"https://doi.org/10.1038/s41413-026-00509-5","url":null,"abstract":"Bone marrow adipocytes are known to have a critical role within the bone marrow niche. However, our understanding of bone marrow adipose tissue expansion with obesity and the role it plays in immune cell regulation and osteoclastogenesis is limited. Here, we showed the expansion of bone marrow adipocytes promoted osteoclast differentiation and subsequently led to obesity-related trabecular and cortical bone loss through a stimulatory effect of the PD-1/PD-L1 axis. Bone marrow adipocytes isolated from obese mice had increased Mcp-1 expression, a key regulator of osteoclastogenesis and myeloid cell accumulation. With the increase in bone marrow adipose tissue-derived Mcp-1, we found an increase in the number of PD-L1+ myeloid cells. While these cells inhibited activated T-cells, we found evidence of a stimulatory osteoclastogenic effect of PD-L1+ myeloid cells on PD-1-expressing osteoclast precursors. The inhibition of PD-1/PD-L1 signaling during early osteoclastogenesis prevented myeloid cell commitment and resulted in decreased cell fusion, supporting the role of PD-1/PD-L1 signaling in osteoclastogenesis. Using a bone marrow adipocyte depletion mouse model (BMAd-Pparg KO), we demonstrated that obese BMAd-Pparg KO mice had a reduced number of bone marrow PD-L1+ myeloid cells, accompanied by a decrease in PD-1+ osteoclast precursors. The reduction in these precursors resulted in fewer osteoclasts, subsequently leading to improved trabecular bone volume. Since osteoclasts are myeloid cell-derived, these results suggest that bone marrow adipocytes are critical for the commitment and differentiation of myeloid cells into osteoclasts. Targeting bone marrow adipogenesis could ameliorate enhanced osteoclastogenesis and provide a novel approach to treat obesity-related bone loss. Obesity-induced expansion of BM adipocytes leads to PD-1/PD-L1-driven osteoclastogenesis and subsequent bone loss in obese, HFD-fed (OB-HFD) mice. After 12 weeks on a HFD, OB-HFD mice had a significant increase in BM adiposity and BMAT-derived Mcp-1 expression. The increase in BMAT-specific Mcp-1 expression was coupled with an increase in PD-1+ osteoclast (OC) precursors and PD-L1+ myeloid cells. In the context of obesity, the PD-1/PD-L1 axis has a stimulatory effect that enhances osteoclastogenesis and leads to trabecular and cortical bone loss. By depleting BM adipocytes with obesity, BMAT-derived Mcp-1 expression was decreased, as well as a decrease in PD-1+ OC precursors and PD-L1+ myeloid cells. This prevented obesity-related trabecular bone loss. Overall, this work demonstrated a strong correlation between BMAT expansion and PD-1/PD-L1-driven osteoclastogenesis as a mechanism for obesity-induced bone loss. (This image was created using BioRender).","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"40 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483349","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":"C/EBPβ dictates postmenopausal FSHβ transcription and blockade of AEP/C/EBPβ pathway alleviates osteoporosis","authors":"Zhongyun Xie, Jianming Liao, Jing Xiong, Zhenlei Zhao, Keqiang Ye","doi":"10.1038/s41413-026-00510-y","DOIUrl":"https://doi.org/10.1038/s41413-026-00510-y","url":null,"abstract":"Follicle-stimulating hormone (FSH), a gonadotropin that rises in post-menopausal females, activates its receptor FSHR to trigger bone loss via increasing bone resorption by osteoclasts. FSH stimulates CCAAT/enhancer binding protein beta (C/EBPβ) /asparagine endopeptidase (AEP) pathway, facilitating neural degeneration in the brain of mouse models with Alzheimer’s disease (AD). However, whether C/EBPβ/AEP pathway feeds back and modulates FSHβ bone resorption action remains elusive. Here we show that C/EBPβ acts as a transcription factor for fshb gene and directly binds its promoter, mediating its mRNA transcription in the pituitary gland. Knocking down C/EBPβ in primary pituitary cells significantly blunts GnRH (gonadotropin-releasing hormone)-induced FSHβ expression. Knockout of C/EBPβ also robustly diminishes FSHβ levels in mice. Inactivation of AEP, either by knockout of AEP or its small molecular inhibitor, antagonizes C/EBPβ and suppresses FSHβ levels, attenuating ovariectomy (OVX)-elicited osteoporosis. Markedly, a specific AEP inhibitor (#11a) displays comparable therapeutic effect as an FDA-approved drug teriparatide in OVX-induced osteoporosis. Hence, these findings support that C/EBPβ dictates FSHβ transcription and blocking AEP by its inhibitor represses C/EBPβ-mediated FSHβ levels, exerting prominent therapeutic efficacy toward osteoporosis.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"20 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465445","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":"Factor VIII restores bone parameters and modulates muscle proteo-metabolome in Factor VIII knockout male mice.","authors":"Antoine Babuty,Javier Muñoz-Garcia,Olivier D Christophe,Laurie Fradet,Manon Taupin,Denis Cochonneau,Emilie Ollivier,Frank Driessler,Claudia Lange,Oleksandr Boychenko,Marie-Françoise Heymann,Dominique Heymann","doi":"10.1038/s41413-025-00485-2","DOIUrl":"https://doi.org/10.1038/s41413-025-00485-2","url":null,"abstract":"In addition to its role in hemostasis, Factor VIII (FVIII) has recently been shown to potentially impact angiogenesis, inflammation, osteopenia, and sarcopenia. This was explored here by studying the musculoskeletal development of FVIII knockout (FVIII-/-) male mice. These animals developed an osteoporotic phenotype with significant bone microarchitectural alteration, reduced vascularization, and a lower osteoblastic population. Proteomic analyses revealed differentiating bone metabolism-related proteins between FVIII-/- and wildtype mice. Weekly infusions of recombinant FVIII protein reversed this phenotype. Surprisingly, younger FVIII-/- mice had heavier muscles with larger fibers, shifted from type IIx to type IIb, not reversed by FVIII treatment. Significant proteomic and metabolomic differences between wildtype and FVIII-/- muscles were observed, some of which were reduced by FVIII treatment. This study provides the first comprehensive full-phenotypic characterization of bones and muscles in FVIII-/- mice and demonstrates the benefits of FVIII supplementation to normalize their musculoskeletal phenotype.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"8 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393992","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":"PRMT6 is required for initiating and amplifying macrophage-induced inflammation in heterotopic ossification by increasing CCL2 expression.","authors":"Wenxiang Chu,Weilin Peng,Zhengqiang Wu,Yu Xiong,Zhongya Gao,Yang Li,Bangke Zhang,Liang Wang,Haibin Wang,Chaofeng Han,Xuhua Lu","doi":"10.1038/s41413-026-00512-w","DOIUrl":"https://doi.org/10.1038/s41413-026-00512-w","url":null,"abstract":"Heterotopic ossification (HO) is a debilitating disorder marked by ectopic bone formation in soft tissues, frequently triggered by inflammation after trauma. While macrophage-driven inflammation plays a critical role in HO pathogenesis, the molecular mechanisms governing its initiation, amplification and resolution remain elusive. Using a trauma/burn injury (TBI)-induced mouse model of HO, we identified rapid and sustained macrophage accumulation at the injury site during the early inflammatory phase, and macrophage depletion markedly suppressed HO formation. Transcriptomic profiling identified a pronounced upregulation of protein arginine methyltransferase 6 (PRMT6) in macrophages following injury. Genetic deletion or macrophage-targeted knockdown of Prmt6 reduced macrophage accumulation and significantly attenuated HO, without impairing tendon repair. Consistently, pharmacological inhibition of PRMT6 suppressed HO only when administered during the early inflammatory phase, indicating a restricted therapeutic window. Mechanistically, PRMT6 amplified macrophage chemotactic signaling by transcriptionally and epigenetically upregulating CCL2. Genetic disruption of macrophage-derived CCL2 phenocopied Prmt6 deficiency, whereas CCL2 supplementation rescued macrophage recruitment and partially restored HO in Prmt6-deficient mice. At the molecular level, PRMT6 formed a coactivation complex with NF-κB and catalyzed H3R17 asymmetric dimethylation at the Ccl2 promoter, thereby promoting sustained chemokine expression. Collectively, our findings identify PRMT6 as a central epigenetic amplifier of macrophage-driven inflammation that links early injury responses to ectopic bone formation. Targeting PRMT6 during the early inflammatory phase represents a promising strategy to prevent HO while preserving physiological tissue repair.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"16 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147381373","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":"The spinal lymphatic system: an emerging pathway bridging fluid homeostasis, immunity, and disease.","authors":"Yubao Hou,Jianwei Wu,Shuo Yang,Hongwei Wang,Xianghe Wang,Zian Lu,Zhenhao Chen,Jing Feng,Hongli Wang","doi":"10.1038/s41413-026-00508-6","DOIUrl":"https://doi.org/10.1038/s41413-026-00508-6","url":null,"abstract":"The lymphatic system, traditionally regarded as a unidirectional conduit for interstitial fluid and immune cell transport, has recently been redefined through the discovery of lymphatic networks along the spinal axis. These spinal lymphatic vessels, encompassing the spinal cord, vertebral bones, and intervertebral discs, challenge long-standing anatomical dogmas and introduce new perspectives on the interplay between the central nervous system (CNS) and the vertebral column. This review systematically summarizes the distribution and dual functions of the spinal lymphatic system in regulating cerebrospinal fluid drainage, maintaining tissue homeostasis, and mediating immune responses. Furthermore, we highlight emerging evidence linking spinal lymphatic dysfunction to spinal pathologies, neurological disorders, and vertebral degeneration. Based on these findings, we propose that the spinal lymphatic system constitutes a previously underappreciated pathway integrating spinal cord and vertebral physiology, with potential implications for both disease progression and therapeutic intervention. While research on the cranial lymphatic system has rapidly advanced, the spinal lymphatic system remains comparatively underexplored. We hope this review will catalyze further investigation into spinal lymphatic biology and inform the development of novel therapeutic strategies targeting spinal and neurological diseases.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"245 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350525","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":"TGF-β-induced fibrotic scar formation limits recovery of spinal cord injury.","authors":"Dayu Pan, Panfeng Wu, Kathleen Noller, Patrick Cahan, Xu Cao","doi":"10.1038/s41413-026-00507-7","DOIUrl":"10.1038/s41413-026-00507-7","url":null,"abstract":"<p><p>Spinal cord injury (SCI) often causes long-term disability. But effective means to promote proper regeneration after SCI has so far failed to reach the clinic. Here, we report that fibrotic scar formation at injury sites prevents recovery after SCI and that the inhibition of fibrotic scar formation significantly improved SCI recovery in adult mice. We found that after SCI there is an elevation of macrophages, which are a primary source of activated transforming growth factor-β 1 (TGF-β1) that in turn recruits mesenchymal stromal/stem cells (MSCs) to induce their fibroblast differentiation, thus promoting scar formation. We also found that activated TGF-β1 acts on resident pericytes in the endothelial niche of the blood-spinal cord barrier to promote their differentiation into fibroblasts, which also contributes to scarring. Interrupting these pathways by selective genetic KOs or treatment with a TGF-β-neutralizing antibody inhibited scar formation and improved SCI functional recovery. Notably, we found that neonatal mice recover scarlessly after SCI and with no active TGF-β at the injury site. Together, these findings suggest that fibrotic scarring occurs due to elevated activation of TGF-β, and preventing such activation or neutralizing active TGF-β may be an approach to improve outcome after SCI.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12936232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147302542","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}