Bone Research最新文献

{"title":"Osteocyte-specific gasdermin D deletion accelerates osteoarthritis via promoting subchondral inflammation and remodeling.","authors":"Yuki Ogawa, Taku Ebata, Taiki Tokuhiro, Liyile Chen, Ryota Suzuki, Yuki Fujie, Masaya Nakajo, Tsutomu Endo, Hend Alhasan, Masanari Hamasaki, Daisuke Takahashi, Koji Iwasaki, Ken Kadoya, Tomohiro Onodera, Norimasa Iwasaki, M Alaa Terkawi","doi":"10.1038/s41413-026-00566-w","DOIUrl":"10.1038/s41413-026-00566-w","url":null,"abstract":"<p><p>Subchondral bone remodeling in the early stages of osteoarthritis (OA) is characterized by elevated bone turnover and is closely associated with osteocyte function within the subchondral bone. However, beyond the canonical role of gasdermin D (GSDMD) in mediating pyroptosis in immune cells, its function in osteocytes remains poorly understood. Accordingly, this study aimed to determine whether osteocyte-derived GSDMD regulates subchondral bone homeostasis or contributes to pathological remodeling during osteoarthritis progression. GSDMD expression was evident in osteocytes within the subchondral bone in both clinical and experimental models of OA, as well as in osteocytes co-cultured with stimulated chondrocytes, suggesting a potential role for osteocyte-derived GSDMD in the bone microenvironment. Remarkably, specific deletion of Gsdmd in osteocytes led to increased bone remodeling, which was accompanied by cartilage degeneration in an OA model, as well as bone loss in an osteoporosis model. Mechanistically, Gsdmd-deficient osteocytes displayed enhanced activation of CARD9/NF-κB signaling under inflammatory stimulation, leading to increased production of inflammatory mediators and osteoclastogenic factors that disrupted osteoblast-osteoclast coupling. These changes induced high-turnover subchondral bone remodeling, altered joint mechanical properties, and accelerated cartilage degeneration. Collectively, our findings identify osteocyte-derived GSDMD as an important regulator of subchondral bone remodeling and suggest that loss of this regulatory mechanism exacerbates OA progression. These results further indicate that therapeutic strategies targeting GSDMD should be approached with caution due to potential effects on bone remodeling and inflammatory signaling.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13415536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599135","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":"Osteocalcin-dependent and -independent metabolic dysregulation in a mouse model of Osteogenesis imperfecta.","authors":"Josephine T Tauer,Frank Rauch,Mathieu Ferron,Svetlana V Komarova","doi":"10.1038/s41413-026-00553-1","DOIUrl":"https://doi.org/10.1038/s41413-026-00553-1","url":null,"abstract":"Osteogenesis imperfecta (OI) is a rare bone fragility disorder. Previously, in a severe OI mouse model (Col1a1Jrt/+), a sex- and age-dependent metabolic phenotype was observed, correlating with elevated levels of the bone-derived hormone osteocalcin (OCN). This hormone is known to play a crucial role in managing energy metabolism, including glucose regulation and fat mass. In fact, upon high-fat diet (HFD) exposure, OI mice developed a metabolic syndrome linked to sex and OCN. To assess OCN's role in OI, Col1a1Jrt/+ mice were crossed with OCN-deficient mice (Bglap). Under regular chow and HFD conditions, both OCN-dependent and OCN-independent metabolic alterations were identified. OCN-dependent processes were adipose tissue, liver, and insulin metabolism in a sex-, age-, and diet-dependent manner. OCN-independent traits included the pancreas in juvenile mice, HFD-induced pancreatic insulin levels and glucose intolerance, besides overall growth, fertility, and bone phenotype. Notably, increased juvenile energy expenditure was OCN-independent, while HFD-induced changes were OCN-driven. These findings demonstrate OCN's role in shaping the metabolic phenotype while revealing distinct OCN-independent effects, emphasizing the complex genetic regulation of metabolism in OI.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"13 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148462401","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":"Bispecific antibody against sclerostin and DKK1 improves bone health and reduces bone marrow adipose tissue accumulation in experimental chronic kidney disease.","authors":"Worachet Promruk,Soher N Jayash,Chartinun Chutoe,Hua Zhu Ke,Xiaofeng Liu,Rachel L Wade,Alexander von Kriegsheim,William P Cawthorn,Katherine A Staines,Louise A Stephen,Colin Farquharson","doi":"10.1038/s41413-026-00556-y","DOIUrl":"https://doi.org/10.1038/s41413-026-00556-y","url":null,"abstract":"Chronic kidney disease (CKD) leads to bone loss and bone marrow adipose tissue (BMAT) accumulation. Sclerostin and dickkopf-1 (DKK1) are two inhibitors of Wnt signalling, which suppress bone formation, promote bone marrow adipogenesis, and are elevated in CKD. However, therapies targeting sclerostin have shown limited efficacy in improving bone health in CKD animal models. Herein, we explored whether dual inhibition of sclerostin and DKK1 via a rodent bispecific antibody (rbsAb) could prevent bone loss and suppress BMAT accumulation in a CKD mouse model. CKD was induced using an adenine-supplemented diet in male mice, with CKD and control mice treated weekly for 6-weeks with vehicle or 30 mg/kg body weight of rbsAb. Circulating sclerostin and DKK1 were ~2- and ~3-fold higher, respectively, in CKD mice compared to controls. Proteomic profiling by LC-MS/MS and functional enrichment analysis suggested that in CKD mice, adipogenesis, osteoclast differentiation and bone resorption were increased whereas osteoblast differentiation was inhibited. These changes were prevented by antibody treatment. MicroCT revealed that long bones of CKD mice were characterised by lower bone mineral density, trabecular and cortical bone, and impaired biomechanical properties, but their vertebrae were unaffected. RbsAb treatment prevented cortical and trabecular bone loss and restored biomechanical properties. BMAT, as visualised by microCT imaging of osmium-stained bones, was elevated in CKD but reduced to control levels by rbsAb treatment. In conclusion, dual inhibition of sclerostin and DKK1 improved bone integrity and suppressed BMAT in experimental CKD, suggesting a promising therapeutic avenue for renal osteodystrophy.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"344 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148451808","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":"Fgfr3–Wnt signaling crosstalk is involved in maintaining cranial suture integrity","authors":"Rachel Pereur, Yvan Marc, Yuliya Lim, Alain Schmitt, Marilyne Malbouyres, Anatole Chessel, Florence Ruggiero, Marie-Claire Schanne-Klein, Laurence Legeai-Mallet, Emilie Dambroise","doi":"10.1038/s41413-026-00558-w","DOIUrl":"https://doi.org/10.1038/s41413-026-00558-w","url":null,"abstract":"Cranial suture formation is a dynamic process that requires precise cellular and molecular coordination to regulate bone growth and maintain suture homeostasis. The Fibroblast Growth Factor Receptor 3 (FGFR3) signaling pathway is among the major pathways disrupted in craniosynostosis; however, its precise role during cranial suture formation is still unknown. Using a relevant <italic>fgfr3</italic> LoF zebrafish model exhibiting abnormal suture morphology, we demonstrated for the first time that Fgfr3 plays a pleiotropic role in both the formation and maintenance of cranial sutures. Transmission electron microscopy and second harmonic generation imaging revealed that Fgfr3 is essential for the proper organization of the collagen network within the suture. Using specific transgenic reporter lines, we showed that Fgfr3 is crucial for regulating osteogenesis in this region. Specifically, Fgfr3 limits the number of osteoprogenitors at the osteogenic front and promotes osteoblast maturation at the suture edge. RNAscope analyses further revealed that loss of Fgfr3 led to significant upregulation of <italic>fgf18</italic> expression. Finally, our findings show that loss of Fgfr3 results in the activation of the canonical Wnt pathway, and possibly the BMP pathway, within cranial sutures. Pharmacological inhibition of canonical Wnt signaling during suture development using the β-catenin inhibitor XAV939 restored <italic>fgf18</italic> expression, partially normalized levels of the BMP antagonist <italic>grem1</italic>, reduced SMAD1/5 phosphorylation, and produced a significant improvement in cranial suture morphology. In conclusion, these findings position Fgfr3 as a central regulator of cranial suture formation and homeostasis, acting through intricate cross-talk between the FGF, canonical Wnt, and possibly BMP signaling pathways. These data offer new insights into the biology of cranial suture and FGFR3-related craniosynostoses.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"30 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148612825","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":"Advances in heterogeneity and classification of osteoarthritis.","authors":"Taiyuan Huang,Jianxiong Shu,Zhaoran Wu,Zhong Alan Li,Rocky S Tuan,Changhai Ding,Yao Lu","doi":"10.1038/s41413-026-00549-x","DOIUrl":"https://doi.org/10.1038/s41413-026-00549-x","url":null,"abstract":"Osteoarthritis (OA) is a highly heterogeneous disease that exhibits distinct clinical manifestations and pathological mechanisms in different joints, patients, and even at different disease stages for the same patient. Genetic and pathophysiological factors contribute to the heterogeneity of OA in clinical manifestations, treatment responses, and prognosis of patients. Despite efforts in developing disease-modifying OA drugs and treatment technologies, no current approach can efficiently delay OA progression, and results from clinical research are inconsistent due to the mismatch between treatment mechanisms and heterogeneous patient subtypes. Researchers utilize clinical data to classify OA into different phenotypes based on etiological factors, clinical symptoms, and imaging features, as well as endotypes based on biomarkers, molecular mechanisms, metabolism profiles, and omics analyses, but there is still a lack of unified standards. Therefore, a comprehensive understanding of the heterogeneity and classification of OA is crucial for stratified and personalized treatment. In this Review, we discuss the heterogeneity of OA, with an emphasis on heterogeneity in treatment responses. We provide a structured analysis of current studies of OA classification, offering new perspectives for future OA research and clinical practice.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"9 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148400571","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":"Inhibition of AXL receptor tyrosine kinase increases osteoblast function and bone mass.","authors":"Mubashir Ahmad,Christoph Kölbl,Irfana Jan,Ann-Kristin Dorn,Burak Özkan,Florian Olde Heuvel,Dilay Yilmaz,Alessa Wagner,Maja Vujic Spasic,Benjamin Thilo Krüger,Sooyeon Lee,Francesco Roselli,Anita Ignatius,Jan Tuckermann","doi":"10.1038/s41413-026-00554-0","DOIUrl":"https://doi.org/10.1038/s41413-026-00554-0","url":null,"abstract":"Osteoporosis, a prevalent age-related disease, is characterized by impaired bone formation and an increased risk of fractures. Current anabolic treatments primarily rely on biologics, which are costly and require inconvenient administration. Identifying regulators of osteoblastogenesis that are amenable to small-molecule targeting is essential for developing more accessible therapies. Through an unbiased kinome-wide RNAi screen in primary murine calvarial osteoblasts, we identified the AXL receptor tyrosine kinase (Axl) as a negative regulator of osteoblast differentiation. Axl is most highly expressed in undifferentiated and early differentiated osteoblasts, with a rapid decline in expression during osteoblast maturation. siRNA-mediated knockdown of Axl or pharmacological inhibition with the small molecule BGB324 significantly enhanced osteoblast differentiation and mineralization in vitro. In mice, BGB324 treatment significantly increased bone mass by promoting bone formation. Mechanistically, Axl knockdown or inhibition upregulated interferon-stimulated gene 15 (Isg15), while Isg15 knockdown impaired osteoblast differentiation and enhanced Erk phosphorylation, leading to increased expression of osteoblast-specific genes. Consistently, double knockdown experiments demonstrated that simultaneous loss of Axl with either Isg15 or Mapk1, but not other interferon-related genes, reversed the Axl knockdown-induced increase in osteoblast differentiation, reinforcing their mechanistic involvement. Collectively, our study identifies Axl as a promising therapeutic target for osteoporosis and other bone-related disorders.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"72 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148393723","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":"Clec3b+ extraskeletal cells regulate fracture healing and heterotopic ossification.","authors":"Ezgi Aydin,Jacob A Moore,Mark Bubnovich,Gabriel Cuilan,Kristin Gebauer,Brenda Kim,Emily Chu,Ugur M Ayturk","doi":"10.1038/s41413-026-00532-6","DOIUrl":"https://doi.org/10.1038/s41413-026-00532-6","url":null,"abstract":"Bone healing is orchestrated by multiple cell populations, including those that normally do not produce bone but acquire osteoprogenitor capabilities following injury. Muscle-resident fibroadipogenic progenitors (FAPs) and superficial periosteal cells are among such cells, however their physiologic significance in bone healing and the mechanisms regulating their differentiation are unclear. Here, using the new tamoxifen-inducible Clec3b.CreERT2 allele, we show that both of these populations can be traced and manipulated in a mouse model. Clec3b+ cells are completely absent in marrow and bone-lining surfaces and can differentiate to multiple cell types including osteoblasts during fracture repair and BMP2-induced heterotopic ossification. Orthotopic transplantation assays indicate that Clec3b+ FAPs rather than Clec3b+ periosteal cells are mobilized to become osteoblasts in these conditions. Further, Clec3b+ cells appear functionally distinct from periosteal skeletal progenitors as they exhibit remarkably low chondrogenesis during fracture healing; however, they can form cartilage during heterotopic ossification of muscle and ex vivo culture. Inhibition of WNT-signaling or depletion of Clec3b+ cells reduce mineralization during both processes. These data show that extra-skeletal cells that normally do not produce bone, FAPs in particular, are recruited to help repair bone fractures, and could represent a novel target for therapies aimed to enhance fracture healing.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"28 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148393702","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":"Angiogenin mediates cell-cell fusion as a mitochondrial RNA processing enzyme.","authors":"Ke Shen,Yixiang Zeng,Jiekang Wang,Kangping Song,Surendra Kumar,Peisong Gao,Guo-Fu Hu,Xu Cao,Mei Wan","doi":"10.1038/s41413-026-00545-1","DOIUrl":"https://doi.org/10.1038/s41413-026-00545-1","url":null,"abstract":"Cell-cell fusion, essential for diverse physiological events, requires high ATP levels. While mitochondrial activity increases in fusing cells, the mechanism driving mitochondrial ribosome (mitoribosome) biogenesis to support these energy demands remains unclear. Here, we identify angiogenin (ANG) as a mitochondrial tRNA (mt-tRNA) processing enzyme critical for mitoribosome biogenesis during myoblast and osteoclast fusion. Upon fusion initiation, ANG translocates to mitochondria, promoting mitoribosome biogenesis to support translation of respiratory complex proteins for ATP production. Using transcriptome-wide PARE and 5' RACE analyses, we show that ANG cleaves the tRNA 3'-end in mitochondrial pre-RNA transcripts bordering rRNAs and mRNAs, enabling their release for translation. Loss of ANG or disruption of its ribonucleolytic activity impairs osteoclast and myoblast fusion, disrupting bone and muscle homeostasis and skeletal muscle regeneration post-injury. Our findings establish ANG as an essential mitoribosome biogenesis regulator and highlight a novel mechanism of mitochondria energy regulation in high-energy-demand biological processes.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"25 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148349231","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":"Murine model of high bone mass osteogenesis imperfecta exhibits bone matrix hyper-mineralization, misaligned mineral crystals, and altered osteoblast differentiation.","authors":"Aileen M Barnes, M Helen Rajpar, Joseph E Perosky, Stéphane Blouin, Basma Khoury, MaryAnn Weis, Theresa Hefferan, Alberta Derkyi, Gali Guterman-Ram, Ghazal Hedjazi, Kiersten Campbell, Chris Stephan, David R Eyre, Ryan K Dale, Peter Fratzl, Kenneth M Kozloff, Nadja Fratzl-Zelman, Joan C Marini","doi":"10.1038/s41413-026-00531-7","DOIUrl":"10.1038/s41413-026-00531-7","url":null,"abstract":"<p><p>Osteogenesis imperfecta (OI), characterized by bone fragility and low bone mass, is predominantly caused by mutations in type I collagen. High bone mass OI (HBM OI) is a rare form caused by heterozygous missense mutations at the type I procollagen C-propeptide cleavage site. Knock-in HBM OI mice were generated to elucidate the effect of this mutation on cells and bone. HBM OI murine femora contain increased monomeric pro-α1(I)C-propeptide and pC-collagen; their bone collagen fibrils have a \"barbed-wire\" appearance. Decreased C-propeptide cleavage diminishes bone strength. HBM OI femora are extremely brittle, with thin cortices, decreased BV/TV, and fracture load. The cortical bone has increased mineral content, with thinner, more disorganized mineral particles. Increased expression of ossification genes in both murine and human HBM OI osteoblasts during in vitro differentiation and increased mineral deposition in culture indicate impaired C-propeptide processing affects cellular processes related to mineralization, rather than being a passive matrix process. Gene ontology analysis of RNA-seq data from differentiating HBM OI osteoblasts revealed top upregulated pathways for ossification, mineralization, and osteoblast differentiation (5-25×) while top-downregulated pathways involved cellular adhesion, migration, and angiogenesis (5-10×), all related to cell-matrix interactions. Moreover, the HBM matrix affects osteoblast function. WT osteoblasts plated on HBM OI decellularized matrix in vitro showed less punctate vinculin, increased peripheral actin staining, and the presence of lamellipodia, suggesting a decrease in cellular adhesion. Insights into the mechanism of HBM OI mineralization may lead to improved therapies for HBM OI and low bone mass conditions.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13269806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148256769","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":"An ITGA11 expressing subpopulation as predictor for the donor-specific osteogenic capacity of stromal cells.","authors":"Ali Jasim Mohammad Jamil, Kaja Madsen, Souad Daamouch, Birgitte Villadsen, Chao Ma, Shakespeare Jeromdesella, Mikkel Ørnfeldt Nørgård, Emilie Grupe, Maria Bruun Jakobsson, Yuting Wang, Eri Takematsu, Liming Zhao, Stuart Barry Goodman, Lawrence Henry Goodnough, Charles Kwok Fai Chan, Thomas Levin Andersen, Moustapha Kassem, Alexander Rauch","doi":"10.1038/s41413-026-00536-2","DOIUrl":"10.1038/s41413-026-00536-2","url":null,"abstract":"<p><p>Stromal progenitor cells of bone marrow origin are non-hematopoietic cells that give rise to osteoblasts and adipocytes in the postnatal organism. Marrow stromal cells (also known as mesenchymal stem cells - MSCs) are currently being employed in a large number of clinical trials for regenerative purposes post in vitro expansion. However, the clinical outcome has been variable, which might in part be due to the heterogeneity of the cells and the lack of a defined cell product with a molecular signature that favors tissue regeneration. In this study, we determined the cellular heterogeneity of primary stromal cultures and examined how inter-donor variation in subpopulation composition contributes to the differentiation potential of primary cultures. We profiled 136 014 stromal progenitors from 26 donors and identified 5 subpopulations that were linked to distinct bone-related pathways and genetic traits of bone mineral density and morphology. Abundance of one cluster characterized by high expression of ITGA11 (integrin alpha-11) and genes related to matrix function, collagen organization, and elevated expression upon lineage commitment was positively correlated with osteoblastic differentiation capacity in vitro. In addition, ITGA11 protein expression in progenitor cells was a predictive marker for matrix mineralization in vitro and ectopic bone formation in vivo. Sorting stromal progenitors into ITGA11^high and ITGA11^low cells established cultures with high and low osteoblastic differentiation potential and revealed transcriptional differences reflective of the subpopulation-specific signature, which was not affected by siRNA-mediated knockdown of ITGA11 expression. Our findings corroborate the presence of an extensive donor-dependent cellular heterogeneity that persists in cultured stromal cells, and that ITGA11 can be employed as a marker for isolating cells with high bone-forming potential, a feature likely to benefit clinical trials of bone regeneration.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13265797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148249155","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}