Bone Research最新文献

{"title":"Akkermansia muciniphila attenuates intervertebral disc degeneration via extracellular vesicle-mediated delivery of the effector protein B2UKX5.","authors":"Zhe Guan, Xiaoxue Li, Yixiao Chen, Sheng Zhu, Jie Wen, Hongliang Zhou, Chunyuan Chen, Jianghua Liu, Guoqiang Zhu, Zhilin Pang, Yiwei Liu, Ling Jin, Shiyu Zeng, Yi Luo, Xiaoxiao Gong, Yu Yang, Ya Chen, Yang Wu, Meidan Wan, Hao Yin, Yong Zhou, Zhenxing Wang, Hui Xie","doi":"10.1038/s41413-026-00541-5","DOIUrl":"10.1038/s41413-026-00541-5","url":null,"abstract":"<p><p>Low back pain is a leading cause of global disability, with intervertebral disc degeneration (IVDD) as a primary contributor. Emerging evidence suggests a link between gut microbiota and disc health, yet the underlying mechanisms remain unclear. Through Mendelian randomization and a clinical cohort analysis, we identified a causal inverse relationship between Akkermansia muciniphila (Akk) abundance and IVDD risk, with reduced fecal Akk levels correlating with increased IVDD severity. Akk protected against IVDD in microbiota-depleted mice, and this protection was abolished by pharmacologic inhibition of extracellular vesicle (EV) secretion. Consistently, Akk-derived EVs (Akk-EVs) recapitulated the benefits of Akk across natural aging, tail needle puncture, and bipedal standing mouse models, while control bacterium (Escherichia coli) and its EVs did not. Proteomics and functional validation identified B2UKX5 as a key Akk-EV-enriched effector protein. Furthermore, recombinant B2UKX5 attenuated IVDD in vivo and regulated critical pathways for disc homeostasis, including collagen synthesis, extracellular matrix remodeling, and chromatin silencing, as revealed by transcriptomic profiling of microdissected nucleus pulposus and annulus fibrosus tissues. Analysis of clinical samples further confirmed that Akk-EVs and B2UKX5 levels in circulation and intervertebral disc tissues were negatively correlated with IVDD severity. These findings establish a novel gut-disc axis, highlighting Akk, Akk-EVs, and B2UKX5 as promising therapeutic candidates for IVDD prevention and treatment.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13190703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980281","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":"Decoding cellular communication networks and signaling pathways in bone, skeletal muscle, and bone-muscle crosstalk through spatial transcriptomics in a young male mouse.","authors":"Chuan Qiu, Yisu Li, Yun Gong, William Sherman, Di Tian, Weiqiang Lin, Zehui Pan, Boluwatife Afolabi, Vivek Thumbigere, Kuanjui Su, Jeffrey Deng, Yuwei Hou, Shashank Mungasavalli Gnanesh, Zhe Luo, Qing Tian, Fernando Sanchez, Yiping Chen, Hui Shen, Hong-Wen Deng","doi":"10.1038/s41413-026-00520-w","DOIUrl":"10.1038/s41413-026-00520-w","url":null,"abstract":"<p><p>Bone and skeletal muscle are essential components of musculoskeletal system, enabling movement, load-bearing, and systemic homeostasis. These tissues communicate through dynamic bone-muscle crosstalk mediated by cytokines, growth factors, and extracellular-matrix (ECM) proteins. The spatial organization of these mediators is critical for maintaining tissue integrity, and its disruption contributes to diseases, such as osteoporosis, sarcopenia, and metabolic syndrome. Despite this importance, spatial transcriptomics (ST) studies of bone-muscle interactions remain limited. Here, we applied 10x Genomics Visium ST with computational tools, e.g., SMART and CellChat, to deconvolute cell-type composition and characterize cell-cell communication networks and ligand-receptor (L-R) interactions in mouse femur and adjacent skeletal muscle. We identified eight major cell types (erythroid cells, endothelial cells, skeletal muscle cells, osteoblasts, myeloid cells, monocytes/macrophages, mesenchymal stem cells, and adipocytes) with distinct spatial transcriptional profiles and thirteen CellChat-inferred pathways, such as ECM-receptor related (e.g., COLLAGEN, TENASCIN, THBS) and secreted-signaling involved (e.g., VEGF) pathways. Representative L-R pairs include Col1a1/Col1a2-Sdc4, mediating osteoblast-to-muscle interactions, and Col4a1-Sdc4, facilitating muscle-to-osteoblast interactions in COLLAGEN, Tnxb-Sdc4 in TENASCIN, supporting muscle-to-osteoblast/muscle/myeloid/endothelial communication, Comp-Sdc4 in THBS, driving monocyte/macrophage-to-osteoblast/muscle signaling, and Vegfa-Vegfr1/Vegfr2 in VEGF, mediating muscle-to-endothelial/myeloid signaling. Immunostaining validated colocalization of several representative L-R pairs with their corresponding cells. Additionally, independent mouse and human bone scRNA-seq datasets reproduced most of the pathways and L-R pairs identified in ST, underscoring the robustness and cross-species relevance of our findings. Together, we present an initial spatially resolved transcriptome-wide map of bone-muscle intercellular communication, providing novel insights into molecular crosstalk and establishing groundwork for future studies in musculoskeletal disorders.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13187134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970393","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":"A RANKL⁺/CXCR4⁺ B cell population accumulates in bone marrow and causes age-related osteoporosis in mice.","authors":"Jinbo Li, Jinxiao Fan, Zhenqiang Yao, Han Jiao, Rong Duan, James O Sanders, Addisu Mesfin, Lianping Xing, Brendan F Boyce","doi":"10.1038/s41413-026-00525-5","DOIUrl":"10.1038/s41413-026-00525-5","url":null,"abstract":"<p><p>RANKL induces bone loss in part by promoting degradation of TRAF3, levels of which decrease in murine and human bone during aging, but the major cellular sources of RANKL in bone marrow (BM) during aging are unknown. Here, we identify RANKL⁺CXCR4⁺ B cells (RCBs) as a novel major source of RANKL in murine bone. Their numbers are increased in BM of aged WT male mice and adult mice with TRAF3 conditionally deleted in mesenchymal progenitor cells (MPCs), associated with increased expression in BM of the chemokine, CXCL12, indicating that TRAF3 in MPCs limits RCB numbers in BM of young mice. During aging, TGFβ1-induced TRAF3 degradation in MPCs promotes NF-κB-mediated expression of CXCL12, associated with higher numbers of RCBs in BM where they induce bone resorption. In addition, RCBs from aged mice caused bone loss in young NSG mice and, in an ovariectomized mouse model, accelerated osteoclastic bone resorption coupled with TRAF3 reduction and RCB accumulation in BM. Consistent with these findings, administration of the FDA-approved CXCR4 antagonist, plerixafor, reduced RCB numbers in BM and increased bone mass in naturally aged and ovariectomized mice. Reduction of RCB numbers in BM could treat/prevent osteoporosis.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13183972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970337","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":"From complexity to clarity: aging bone marrow niche in bone and blood regeneration and malignancy.","authors":"Nainita Roy, Hanyu Liu, Allison L Horenberg, Arvind P Pathak, Junyu Chen, Saravana K Ramasamy, Martine Cohen-Solal, Aline Bozec, Warren L Grayson, Anjali P Kusumbe","doi":"10.1038/s41413-026-00543-3","DOIUrl":"10.1038/s41413-026-00543-3","url":null,"abstract":"<p><p>The bone marrow niche (BMN) plays a central role in regulating hematopoietic stem-cell (HSC) maintenance, lineage commitment, and immune homeostasis, while also supporting osteogenesis and maintaining skeletal integrity. Once considered static, the BMN is now recognized as a dynamic and responsive microenvironment that integrates local signals and systemic cues to meet physiological demands and respond to stress. Aging causes profound and progressive changes to this niche, leading to functional decline across both hematopoietic and stromal compartments. Recent advances in high-resolution imaging, single-cell and spatial transcriptomics, and in vivo lineage tracing have revealed remarkable heterogeneity and plasticity within the vascular and mesenchymal elements of this niche. Yet, key questions remain unresolved, including the identity and hierarchy of mesenchymal and osteolineage cells, the specialization of subsets of endothelial cells, the integration of systemic regulation, and whether the aging bone marrow acts as a driver or a passenger in malignancy and chronic inflammation. This review revisits current models of the BMN, with a focus on the reciprocal interactions between osteogenic cells and specialized vasculature, and how their disruption during aging impairs hematopoietic output and skeletal remodeling. We also examine how systemic factors such as neural input, metabolic status, and inflammatory signaling influence the aging of the BMN. Finally, we highlight emerging translational platforms, including iPSC-derived bone marrow organoids, engineered niches/hydrogels, and vascularized organ-on-chip systems, that enable mechanistic testing of rejuvenation strategies. Together, these insights have the potential to pave the way toward targeted interventions that restore the function of the BMN and promote healthy aging of the bone and blood systems.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13184274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970377","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":"The endosteal niche regulates breast cancer cell dormancy in bone: identification of new molecular determinants.","authors":"Antonio Maurizi, Maria Salbini, Michela Ciocca, Marzia Rea, Giuseppe D Tocchini-Valentini, Matilde Merolle, Hanna Taipaleenmäki, Christina Møller Andreasen, Manuela Pellegrini, Anna Teti","doi":"10.1038/s41413-026-00535-3","DOIUrl":"10.1038/s41413-026-00535-3","url":null,"abstract":"<p><p>Cellular dormancy compromises the long-term survival of breast cancer patients. Bone represents a frequent site for metastasis, where Spindle-shaped N-cadherin⁺CD45^- osteoblasts (SNOs) hold dormant metastatic cells in the endosteal niche with a Notch2-dependent mechanism. In this work, we excluded the involvement of Notch1 in SNO-induced breast cancer cellular dormancy by immunofluorescence/immunohistochemistry and molecular approaches, using breast cancer tissues and cell lines. RNAdSeq in human bone metastatic MDA-MB231 breast cancer cells sorted for Notch1^HIGH and Notch2^HIGH expression demonstrated that, compared to their low counterpart, only Notch2^HIGH cells expressed enriched pathways relevant for the metastatic process, including pluripotency and Hematopoietic Stem Cell (HSC) gene signatures. They expressed the HSC-associated genes CXCR4, CD34 and TIE2 and MDA-MB231 cells enriched in the encoded proteins showed lesser proliferation ability. Reduced incidence of osteolytic lesions was induced by CXCR4^HIGH cells intratibially injected in immunocompromised mice, while lower lesion extension was induced by CXCR4^HIGH and TIE2^HIGH injected cells compared to CXCR4^LOW and TIE2^LOW cells. Notch2^HIGH cells were enriched in endoplasmic reticulum stress and unfolded protein response genes and overexpressed the CD177 protein, while the CD177 ligands, Plaur, Itgam and Ceacam 1, were highly expressed in SNOs. Kaplan-Meier plots showed positive correlation between high expression of CD177, ITGAM and CEACAM 1 - but not PLAUR - and overall survival of patients. CD177^HIGH cells were also CXCR4^HIGH, CD34^HIGH and Notch2^HIGH and proliferated less than CD177^LOW cells. These results support the relevance of Notch2 in SNO-mediated cellular dormancy and identified new pathways implicated in bone metastatic breast cancer cell quiescence.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13176332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147940061","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":"SphK1/mitophagy axis in cementocytes drives orthodontic root resorption via mitochondrial transfer to osteoclasts.","authors":"Han Wang, Sihang Chen, Shuo Chen, Chengchen Duan, Li Zhu, Hengyi Lin, Shujuan Zou, Yu Li, Peipei Duan","doi":"10.1038/s41413-026-00538-0","DOIUrl":"10.1038/s41413-026-00538-0","url":null,"abstract":"<p><p>Orthodontically induced inflammatory root resorption (OIIRR) is a prevalent complication driven by excessive mechanical force, yet the underlying mechanisms linking mechanotransduction to osteoclast activation remain elusive. Here, we identify a novel signaling axis wherein sphingosine kinase 1 (SphK1) in cementocytes translates heavy orthodontic force into a pro-osteoclastogenic signal via mitophagy-mediated mitochondrial transfer. In vivo, heavy force induced OIIRR and upregulated mitophagy markers in cementocytes. In vitro, heavy compression force triggered SphK1-dependent mitophagy in IDG-CM6 cementocytes, as evidenced by increased mitophagosome formation, co-localization of mitochondria with lysosomes, and elevated PINK1/PARKIN signaling. Inhibition of SphK1, either pharmacologically or genetically, suppressed this mitophagic response. Conditioned media from force-loaded cementocytes enhanced osteoclast differentiation and glycolytic metabolism, effects that were abolished by SphK1 inhibition and rescued by a mitophagy agonist. Crucially, we demonstrated that heavy force promotes the transfer of mitochondria from cementocytes to osteoclast precursors, a process dependent on mitophagy. This transferred mitochondrial cargo functioned as a metabolic subsidy, boosting osteoclast bioenergetics and resorptive activity. Our findings unveil the SphK1-mitophagy-mitochondrial transfer axis as a fundamental mechanism of cementocyte-osteoclast communication, positioning SphK1 as a promising therapeutic target to prevent OIIRR.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13176349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147940097","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":"Mineralized DNA tetrahedron-structured hydrogels: a dual-functional Scaffold for immunomodulation and bone regeneration.","authors":"Lan Yao, Jiafei Sun, Zhiqiang Liu, Jiale Liang, Yun Wang, Ye Chen, Ruiqing Wang, Tao He, Yichen Yang, Yao He, Yunfeng Lin, Taoran Tian","doi":"10.1038/s41413-026-00530-8","DOIUrl":"10.1038/s41413-026-00530-8","url":null,"abstract":"<p><p>Clinical limitations of autografts and allografts have driven advances in bone tissue engineering. Emerging biomaterials offer tunable mechanical and bio-regenerative properties for bone reconstruction. DNA hydrogels have attracted increasing attention due to their extracellular matrix-like architecture and excellent cargo-loading capacity. However, their rapid degradation and limited immunomodulatory activity have hindered their long-term efficacy in bone regeneration. To address these limitations, a mineralized tetrahedral framework nucleic acids (tFNAs) hydrogel (Cap-gel) was engineered to integrate early immunoregulation with sustained osteogenic activity. The stable and programmable spatial structure of tFNAs not only promotes macrophage polarization toward the M2 phenotype by presenting immunomodulatory ligands but also serves as a nucleation template for calcium phosphate crystallization, leading to the formation of nano-mineralized structures with controlled morphology. In vitro, Cap-gel promoted osteogenic differentiation via both immune-dependent and independent pathways, while in vivo, it modulated early immune responses and accelerated bone regeneration in a calvarial defect model. In summary, this study introduces a novel tFNA-based mineralized DNA hydrogel system that integrates immunomodulation and osteogenesis, providing a promising strategy for enhanced bone repair in tissue engineering applications. A mineralized DNA hydrogel is constructed by sticky-end self-assembly of tetrahedral framework nucleic acids followed by calcium-phosphate deposition. The hydrogel exhibits antioxidant, immunomodulatory, and osteoinductive properties, enabling sequential regulation of the bone healing microenvironment and effectively promoting cranial defect regeneration.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13156309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855691","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":"Targeting adipocyte ESRRA alleviates osteoarthritis via interrupting inter-organelle crosstalk of complement C3-CFD-MAC cascade.","authors":"Tongling Huang, Zihui Wang, Lu Gao, Jun Gao, Zhaocheng Lu, Pengda Li, Chon Him Choy, Zhuolei Yuan, Yanting Zhong, Chang-An Geng, Huaiyu Wang, Kelvin W K Yeung, Bin Li, Haobo Pan, Di Chen, Min Guan","doi":"10.1038/s41413-026-00527-3","DOIUrl":"10.1038/s41413-026-00527-3","url":null,"abstract":"<p><p>Osteoarthritis is an aging-related systemic disease involving the crosstalk of multiple organs/tissues in metabolism and inflammation, yet little is known about the contribution of liver and marrow adipose tissue (MAT). Here we show that MAT-derived complement factor D (CFD) and component 3 (C3) derived from steatotic liver coordinately drive excessive alternative complement activation, resulting in cartilage damage in mice during aging and metabolic disorders. Mechanistically, estrogen-related receptor α (ESRRA) transcriptionally upregulates CFD responding to bone marrow adipocytes (BMAds) expansion. Inhibition of ESRRA/CFD signaling in BMAds blocks the chondrocyte senescence and catabolism triggered by C3 that is released from steatotic hepatocyte, interrupting C3-CFD-MAC cascade, thereby suppressing ERK1/2 phosphorylation and mitochondrial dysfunction. Adipocyte-specific ablation or pharmacological inhibition of ESRRA reduces CFD levels particularly in adipocyte-rich bone marrow, attenuating osteoarthritis progression in aged mice. Our findings highlight a key liver-MAT-cartilage axis bridged by C3-CFD-MAC pathway, raising the potential for adipocyte ESRRA-targeting therapies for aging-related metabolic osteoarthritis.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13128952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147762129","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":"Vitamin K-dependent carboxylation in osteoblasts regulates bone resorption through GAS6 in male mice.","authors":"Monica Pata, Diep Ngoc Thi Pham, Julie Lacombe, B Ashok Reddy, Young Woong Kim, Abeer Gamal Ali Ahmed, Monzur Murshed, Mathieu Ferron","doi":"10.1038/s41413-026-00528-2","DOIUrl":"10.1038/s41413-026-00528-2","url":null,"abstract":"<p><p>Studies in humans suggest that vitamin K is involved in the regulation of bone remodeling, but the precise mechanism at play remains unknown. In cells, vitamin K functions as a co-factor for the γ-glutamyl carboxylase (GGCX), an enzyme responsible for the conversion of glutamic acid residues (Glu) into γ-carboxyglutamic acid (Gla) residues in secreted proteins. We aim here at determining the role of γ-carboxylation in bone remodeling and at identifying the Gla protein(s) involved. We show that male mice lacking γ-carboxylation specifically in osteoblasts (Ggcx^flox/flox;OCN-Cre) have increased bone mass at 6 months of age due to a reduced number of multinucleated bone resorbing osteoclasts. In co-culture experiments, Ggcx-deficient osteoblasts were less effective than control osteoblasts at supporting osteoclast formation. Among known Gla proteins, we identify GAS6 as an osteoblast-secreted γ-carboxylated factor which signals to differentiating osteoclasts. The GAS6 receptors MerTK and AXL are expressed in pre-osteoclasts and pharmacological inhibitors of AXL and MerTK block osteoclast generation in co-culture. Conversely, recombinant γ-carboxylated GAS6 dose-dependently increases the size of osteoclasts and the number of nuclei per osteoclast in culture. GAS6 marginally affected the induction of osteoclast-specific genes during osteoclast differentiation but significantly increased pre-osteoclast fusion. Finally, increasing bone marrow GAS6 level in transgenic male mice was sufficient to increase the number and size of osteoclasts and to decrease bone mass. This work identifies GAS6 as a novel osteoblast-derived vitamin K-dependent protein regulating osteoclast maturation.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13121459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147762070","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":"Loss of PTH 1 receptor signaling in periodontal cells drives cementum dysfunction and molar ankylosis in mice.","authors":"Hakan Turkkahraman,Carson Joseph Walton,Tianli Zhu,Nisreen Akel,Silvia Marino,Xue Yuan,Teresita M Bellido","doi":"10.1038/s41413-026-00533-5","DOIUrl":"https://doi.org/10.1038/s41413-026-00533-5","url":null,"abstract":"Parathyroid hormone 1 receptor (PTH1R) signaling is critical for mineral ion homeostasis and skeletal development. Although its role in tooth root formation and eruption is established, its specific functions in adult periodontal tissues and craniofacial integrity remain incompletely defined. Here, we investigated the craniofacial and dentoalveolar phenotypes of mice with conditional deletion of PTH1R in DMP1-Cre-expressing cells. DMP1-Cre;PTH1Rfl/fl mutant mice exhibited craniofacial alterations, including reduced maxillary length and defects in the alveolar bone surrounding the molars, as revealed by micro-computed tomography and histological analysis. The mutant mice also displayed severe periodontal ligament (PDL) loss and extensive molar ankylosis, characterized by the direct fusion of alveolar bone to tooth roots, predominantly in regions of acellular cementum. In contrast, incisor development remained unaffected. PTH1R deficiency also resulted in pathological cementum overgrowth, disrupted PDL fiber organization, and decreased expression of key PDL matrix proteins, as evidenced by immunohistochemical and molecular analyses. Mechanistically, the loss of PTH1R enhanced Smad3 phosphorylation and upregulated Osterix, thereby promoting aberrant cementoblast differentiation and mineralization. Concurrently, Dkk1 expression was increased, leading to suppressed Wnt signaling. This evidence establishes PTH1R signaling in cementocytes as a central safeguard of cementum homeostasis and PDL integrity and demonstrates that its disruption induces pathological root-bone fusion and craniofacial abnormalities. These findings advance our understanding of the molecular mechanisms underlying adult periodontal tissue maintenance and open new opportunities for developing therapeutic strategies against ankylosis and related disorders by targeting PTH1R signaling.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"156 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751272","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}