Bone最新文献

{"title":"Models of myeloma bone disease: In vivo and in vitro approaches","authors":"Jiaxian Wang ,&nbsp;Sonja Zweegman ,&nbsp;Richard W.J. Groen","doi":"10.1016/j.bone.2026.117789","DOIUrl":"10.1016/j.bone.2026.117789","url":null,"abstract":"<div><div>This review focuses on experimental models developed to study myeloma bone disease (MBD), a major cause of morbidity in multiple myeloma (MM). Under physiological conditions, bone remodeling is regulated by osteoclasts (OCs) and osteoblasts (OBs); in MM, this balance is disrupted, resulting in enhanced bone resorption and suppressed bone formation. Myeloma cells alter the bone marrow (BM) microenvironment by increasing the RANKL/OPG ratio and secreting Wnt pathway inhibitors such as DKK-1 and sclerostin, thereby promoting osteoclastogenesis and inhibiting osteoblast differentiation. To dissect these mechanisms and evaluate therapeutic strategies, diverse preclinical systems have been developed. Syngeneic murine models, notably the 5T series, remain the most established for reproducing both osteolysis and impaired bone formation, though interspecies differences limit translational relevance. Humanized mouse systems and three-dimensional (3D) in vitro models increasingly address these constraints by incorporating human stromal and hematopoietic elements. Emerging induced pluripotent stem cell–derived bone marrow organoids (iBMOs) offer a fully human platform capable of modeling both osteoclast and osteoblast dynamics. While current iBMOs lack mineralized bone and mature vascular or immune components, advances in differentiation control and matrix engineering are expected to bridge these gaps, providing physiologically relevant and ethically sustainable models for studying MBD and testing therapeutic interventions.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117789"},"PeriodicalIF":3.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nutraceuticals in orthopedic implant osseointegration: Mechanisms, evidence, and clinical perspectives","authors":"Gabriele Ricciardi ,&nbsp;Domenico Donadio ,&nbsp;Giovanni Ficarra ,&nbsp;Chiara Nasso ,&nbsp;Pietro Foglia ,&nbsp;Alessandra Bitto ,&nbsp;Rosa Scarfì ,&nbsp;Guido Fadda ,&nbsp;Flavio Corpina ,&nbsp;Erica Cutè ,&nbsp;Maurizio Martini ,&nbsp;Marco Ferlazzo","doi":"10.1016/j.bone.2026.117801","DOIUrl":"10.1016/j.bone.2026.117801","url":null,"abstract":"<div><div>Total joint replacement is one of the most successful interventions in modern orthopedics, but long-term outcomes depend on effective osseointegration. Pharmacological strategies such as bisphosphonates, estrogens, and monoclonal antibodies can enhance bone–implant integration, but their clinical use is limited by adverse effects. Nutraceuticals, including polyphenols, carotenoids, and polyunsaturated fatty acids, have emerged as promising adjuncts to support bone health and osseointegration, thanks to their safety profile and biological activity. This review summarizes the molecular mechanisms involved in osseointegration, analyzes preclinical and clinical evidence on nutraceuticals, and critically assesses their translational potential. These compounds promote osteoblastogenesis, inhibit osteoclast differentiation, and mitigate oxidative stress, thereby improving peri-implant bone stability. Despite encouraging results, the clinical translation of nutraceuticals remains limited. Most available data are preclinical or based on surrogate endpoints such as bone mineral density, whereas true clinical success is determined by bone-to-implant contact and implant survival, which are rarely investigated in randomized controlled trials (RCTs). Advances in bioavailability strategies (liposomes, nanoemulsions, nanostructured lipid carriers) may improve systemic exposure, but future research must standardize dosages and provide high-quality RCTs to clarify the role of nutraceuticals as complementary tools in orthopedic implant surgery.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117801"},"PeriodicalIF":3.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146032050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Osteoblastic cell responses to zoledronate treatment in-vitro: A systematic review","authors":"Maria Florez-Martin,&nbsp;Adriana-Monica Radu,&nbsp;Kaveh Shakib,&nbsp;Gavin Jell","doi":"10.1016/j.bone.2026.117796","DOIUrl":"10.1016/j.bone.2026.117796","url":null,"abstract":"<div><h3>Background:</h3><div>Zoledronate (ZOL), a potent nitrogen-containing bisphosphonate (BP), is widely prescribed for osteoporosis and metastatic bone disease. While osteoclast inhibition is central to ZOL’s therapeutic action and to the pathophysiology of medication-related osteonecrosis of the jaw (MRONJ), less is known about its direct effects on osteoblasts. Understanding dose- and time-dependent osteoblastic responses is essential for improving <em>in-vitro</em> modelling and informing regenerative strategies.</div></div><div><h3>Methods:</h3><div>We performed a systematic review of <em>in-vitro</em> studies reporting osteoblastic responses to ZOL, adhering to PRISMA guidelines (protocol registered, DOI:10.17605/OSF.IO/GWDP5). Web of Science and Scopus searches identified 606 records, of which 77 met inclusion criteria. Data were extracted for proliferation, metabolic activity, apoptosis, alkaline phosphatase (ALP), biomineralisation, collagen formation, and angiogenesis. Statistical comparisons assessed dose- and time-dependent effects.</div></div><div><h3>Results:</h3><div>Across 2057 datapoints, undesirable outcomes (reduced metabolic activity or proliferation, increased apoptosis) occurred at median [ZOL] of 10 <span><math><mi>μ</mi></math></span>M, significantly higher (<span><math><mrow><mi>p</mi><mo>≤</mo><mn>0</mn><mo>.</mo><mn>0001</mn></mrow></math></span>) than concentrations associated with no effect (1 <span><math><mi>μ</mi></math></span>M) or beneficial responses (0.75 <span><math><mi>μ</mi></math></span>M). Desirable nanomolar-dose outcomes were infrequent and inconsistent across studies. ALP and biomineralisation were dose-dependently impaired, whereas collagen synthesis was unaffected. At 48–71 h, osteoblasts tolerated higher ZOL concentrations compared to later timepoints (<span><math><mrow><mi>p</mi><mo>≤</mo><mn>0</mn><mo>.</mo><mn>05</mn></mrow></math></span>). Media composition influenced responses, with higher calcium (<span><math><mo>≥</mo></math></span>1.8 mM) media protective of negative effects, likely due to ZOL–Ca complex formation.</div></div><div><h3>Conclusion:</h3><div>ZOL exerts direct, dose-dependent inhibitory effects on osteoblasts <em>in-vitro</em>, with outcomes influenced by exposure time and media composition. This review highlights the need for standardised protocols and provides quantitative guidance for modelling MRONJ and testing regenerative interventions.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117796"},"PeriodicalIF":3.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated methylome and hydroxymethylome analysis identifies CAMK2G, NFATC4, and SFRP2 as TET1-regulated drivers of odontoblastic differentiation in human dental pulp cells","authors":"Qimeng Li ,&nbsp;Jinling Li ,&nbsp;Deqian Zhang ,&nbsp;Qiong Xu","doi":"10.1016/j.bone.2026.117775","DOIUrl":"10.1016/j.bone.2026.117775","url":null,"abstract":"<div><h3>Aim</h3><div>DNA 5-methylcytosine (5mC) dynamics are pivotal for tooth differentiation. However, the 5mC landscape during human dental pulp cell (hDPCs) odontoblastic differentiation and the role of Ten-eleven translocation 1 (TET1)-mediated 5mC regulation remain unclear. This study aimed to characterize methylation dynamics and identify TET1-regulated drivers of odontoblastic differentiation.</div></div><div><h3>Methodology</h3><div>Genome-wide DNA methylation was profiled by microarray, and hydroxymethylation changes after TET1 knockdown were assessed by hMeDIP-seq.</div></div><div><h3>Results</h3><div>Methylation and demethylation maintained a dynamic equilibrium during odontoblastic differentiation. A total of 9752 differentially methylated genes were identified and were enriched in pathways related to mesenchymal stem cell and ameloblast differentiation and neurotrophin signaling. hMeDIP-seq demonstrated that TET1 knockdown in hDPCs resulted in 2237 peaks with decreased 5-hydroxymethylcytosine (5hmC) levels and 3285 peaks with increased 5hmC levels compared to controls, corresponding to 1477 hypo-hydroxymethylated genes and 1905 hyper-hydroxymethylated genes. Integrated analysis of hypo-methylated genes and hypo-hydroxymethylated genes identified 88 overlapping candidates. Functional enrichment analyses highlighted tooth mineralization, osteoblast differentiation, TGF-β, and Wnt pathways. Among these, CAMK2G, NFATC4, and SFRP2 were specifically enriched in Wnt signaling and exhibited reduced 5hmC levels after TET1 knockdown. scRNA-seq data further confirmed increased expression of these three genes during odontoblast differentiation.</div></div><div><h3>Conclusions</h3><div>This study delineated the genome-wide DNA methylation landscape during odontoblastic differentiation and identifies CAMK2G, NFATC4, and SFRP2 as novel TET1-regulated epigenetic drivers via 5hmC modification. These findings highlight potential therapeutic targets for epigenetic intervention in dentin regeneration and dental tissue engineering.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117775"},"PeriodicalIF":3.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improvements in bone quality by parathyroid hormone treatment are enhanced in the Nmp4 knockout mouse model","authors":"Runkang Chen ,&nbsp;Bowen Wang ,&nbsp;Samuel J. Stephen ,&nbsp;Joseph P. Bidwell ,&nbsp;Deepak Vashishth","doi":"10.1016/j.bone.2026.117800","DOIUrl":"10.1016/j.bone.2026.117800","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Osteoporosis is linked to increased bone fragility. Unlike anti-resorptive therapies, the analogue of parathyroid hormone, PTH &lt;span&gt;&lt;span&gt;[1]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[2]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[3]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[4]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[5]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[6]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[7]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[8]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[9]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[10]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[11]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[12]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[13]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[14]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[15]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[16]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[17]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[18]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[19]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[20]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[21]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[22]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[23]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[24]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[25]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[26]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[27]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[28]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[29]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[30]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[31]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[32]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[33]&lt;/span&gt;&lt;/span&gt;, &lt;span&gt;&lt;span&gt;[34]&lt;/span&gt;&lt;/span&gt;, is an FDA-approved therapeutic for osteoporosis that enhances bone formation. However, as PTH treatment potency declines over time, it is necessary to investigate the mechanisms involved in this attenuation to reinforce its long-term efficacy. This need has led to investigations into the transcription factor nuclear matrix protein 4 (&lt;em&gt;Nmp4&lt;/em&gt;), in which PTH treatment of mice globally lacking &lt;em&gt;Nmp4&lt;/em&gt; (&lt;em&gt;Nmp4&lt;/em&gt;&lt;sup&gt;&lt;em&gt;−/−&lt;/em&gt;&lt;/sup&gt;) enhanced bone formation. Yet, the changes in the compositional quality of PTH-stimulated bone in &lt;em&gt;Nmp4&lt;/em&gt;&lt;sup&gt;&lt;em&gt;−/−&lt;/em&gt;&lt;/sup&gt; mice are unknown, which in turn could impact the efficiency of this approach. To this end, we characterized cortical bone quality in &lt;em&gt;Nmp4&lt;/em&gt;&lt;sup&gt;&lt;em&gt;−/−&lt;/em&gt;&lt;/sup&gt; mice and wild-type littermates treated with PTH for 8 weeks, starting at 16 weeks of age, using micro-computed tomography, Raman spectroscopy, X-ray diffraction, biochemical assays, and biomechanical characterization (whole-bone strength, fracture toughness). PTH treatment and &lt;em&gt;Nmp4&lt;/em&gt; ablation increased tissue and marrow area and maximum moment of inertia. Femora from PTH-treated mice exhibited increased stiffness, maximum load, and fracture resistance. Bone in &lt;em&gt;Nmp4&lt;/em&gt;&lt;sup&gt;&lt;em&gt;−/−&lt;/em&gt;&lt;/sup&gt; mice with PTH treatment demonstrated lower mineral crystallinity, decreased mineral-to-matrix ratio, lattice spacing, altered levels of advanced glycation end-products, increased levels of osteocalcin, and increased matrix phosphorylation levels. These results suggest that ablation of &lt;em&gt;Nmp4,&lt;/em&gt; in concert with PTH treatment, improved bone function by modulating bone structure and matrix composition. Our findings demonstrate the potential utility of targeting &lt;em&gt;Nmp4&lt;/em&gt; to improve PTH potency and bone qual","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117800"},"PeriodicalIF":3.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146020961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ITAM–Syk signaling mediates the rebound phenomenon after anti-RANKL antibody discontinuation","authors":"Hotaka Ishizu ,&nbsp;Tomoka Hasegawa ,&nbsp;Tomohiro Shimizu ,&nbsp;Tomomaya Yamamoto ,&nbsp;Tsuyoshi Asano ,&nbsp;Norimasa Iwasaki ,&nbsp;Norio Amizuka","doi":"10.1016/j.bone.2026.117776","DOIUrl":"10.1016/j.bone.2026.117776","url":null,"abstract":"<div><div>Rebound bone loss following discontinuation of antiresorptive therapy, especially denosumab, represents a major clinical issue due to rapid osteoclast activation and increased fracture risk. However, the molecular basis of this phenomenon remains poorly understood. In this study, we investigated the role of the DAP12/TREM2–Syk signaling pathway in rebound-associated bone resorption using a murine model treated with and withdrawn from a RANKL-neutralizing antibody. Wild-type (WT) mice exhibited marked rebound bone loss, with elevated expression of DAP12/TREM2-related genes (<em>Tyrobp</em> and <em>Trem2</em>), increased infiltration of CD206⁺ M2 macrophages, and enhanced osteoclast formation. In contrast, DAP12/DAP10 double-knockout (DKO) mice showed diminished osteoclast activity, reduced M2 macrophage presence, and preserved bone mass, indicating the essential role of this signaling axis. Furthermore, pharmacological inhibition of Syk in WT mice effectively prevented rebound bone loss without disturbing normal bone turnover. Histological and ultrastructural analyses revealed hyperactive osteoclasts with enlarged ruffled borders in WT but not in DKO mice. These results identify the DAP12/TREM2–Syk pathway as a key regulator of pathological osteoclast activation after anti-RANKL therapy withdrawal, suggesting that its inhibition may provide a novel therapeutic approach to prevent rebound bone loss while maintaining physiological bone remodeling.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117776"},"PeriodicalIF":3.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"COVID-19 increases the risk for hip fractures in older subjects – A register-based Swedish population study","authors":"Kristina Kajba ,&nbsp;Yiyi Xu ,&nbsp;Ailiana Santosa ,&nbsp;Maria Bygdell ,&nbsp;Claes Ohlsson ,&nbsp;Fredrik Nyberg ,&nbsp;Huiqi Li","doi":"10.1016/j.bone.2026.117811","DOIUrl":"10.1016/j.bone.2026.117811","url":null,"abstract":"<div><div>Hip fractures are a significant public health concern, associated with high morbidity and mortality. This population-based cohort study investigated whether COVID-19 increased hip fracture risk in Swedish adults. The study included 3,931,893 Swedish residents aged ≥50 years as of January 1st 2020, and recorded 50,883 incident hip fractures during follow-up, until the end of 2022. The exposure of interest was COVID-19 confirmed via national registries during the study period, with 711,879 (18.1%) identified cases. The primary outcome was hip fracture incidence. Secondary outcomes included fractures of the proximal humerus and wrist. Association between COVID-19 and fractures was estimated using Cox proportional hazards regression with time-varying exposure, adjusting for demographic and socioeconomic characteristics, frailty index, previous comorbidities, prior medication use, and COVID-19 vaccination status. Results were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). In fully adjusted models, COVID-19 was associated with a 43% higher risk of hip fractures (HR 1.43, 95% CI 1.36–1.50), with stronger association observed in men (HR 1.57, 95% CI 1.45–1.71) than in women (HR 1.36, 95% CI 1.28–1.45). Age-stratified analyses revealed significant associations in individuals aged ≥65 years (men: HR 1.68, 95% CI 1.54–1.82; women: HR 1.42, 95% CI 1.33–1.51), but not in those aged 50–65 years. Associations with proximal humerus and wrist fractures were less pronounced. These findings suggest that COVID-19 is associated with a substantially increased risk of hip fracture, especially among individuals aged ≥65 years old, underscoring the importance of targeted fracture prevention in this group after COVID-19.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117811"},"PeriodicalIF":3.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prmt1-mediated methylation of Ddx17 promotes osteoblast differentiation via regulating the alternative splicing of Sh2b1","authors":"Xinluan Jiang ,&nbsp;Bilan Li ,&nbsp;Yunfei Ma ,&nbsp;Jiaxin Huang ,&nbsp;Chengwei Gu ,&nbsp;Yucui Jin ,&nbsp;Huimin Ding ,&nbsp;Changyan Ma","doi":"10.1016/j.bone.2026.117798","DOIUrl":"10.1016/j.bone.2026.117798","url":null,"abstract":"<div><div>Osteoporosis (OP) is characterized by impaired osteoblast-mediated bone formation and reduced mineralization, which increases fracture risk and challenges global skeletal health. Ddx17 (DEAD-box helicase 17) is implicated in multiple cancers, but its role and mechanism in bone biology, especially in osteoblast differentiation and osteoporosis pathogenesis remain unclear. In this study, we demonstrated that Ddx17 expression was significantly reduced in trabecular bones of patients with osteoporosis. During osteoblastic differentiation of MC3T3-E1 and C3H10T1/2 cells, Ddx17 expression levels increased gradually in a time-dependent manner. Loss-of-function and gain-of-function experiments revealed that Ddx17 promoted osteoblast proliferation and differentiation. Mechanistically, Ddx17 was a direct substrate of Prmt1 (protein arginine methyltransferase 1), which specifically catalyzed ADMA modification of Ddx17 at R426, thereby enhancing Ddx17 protein stability. Stabilized Ddx17 modulated the alternative splicing of Sh2b1 mRNA, thereby promoting the expression of Sh2b1-T1 while suppressing that of Sh2b1-T2. Rescue experiments demonstrated that re-expression of Sh2b1-T1, but not Sh2b1-T2, reversed the impairment of osteoblast differentiation triggered by Ddx17 knockdown. Taken together, these findings underscore the critical role of the Prmt1-Ddx17-Sh2b1 axis in regulating osteoblast differentiation and suggest this axis as a promising therapeutic target for osteoporosis.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117798"},"PeriodicalIF":3.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gαs variant detection discerns skeletal cell types involved in fibrous dysplasia pathogenesis","authors":"Zachary Michel ,&nbsp;Vivian MacDonald ,&nbsp;Aleena Arif ,&nbsp;Ibrahim I. Elbashir ,&nbsp;Jonathan Freeman ,&nbsp;Zubeyir H. Gun ,&nbsp;Charles Osamor ,&nbsp;Jocelyn Taylor ,&nbsp;Michael T. Collins ,&nbsp;Kelly L. Roszko ,&nbsp;Luis F. de Castro ,&nbsp;Vardit Kram ,&nbsp;Alison M. Boyce","doi":"10.1016/j.bone.2026.117792","DOIUrl":"10.1016/j.bone.2026.117792","url":null,"abstract":"<div><div>Fibrous dysplasia (FD) is a mosaic disorder caused by activating Gα_s variants. Skeletal stem cells give rise to abnormal osteoprogenitors, resulting in fibro-osseous lesions with prominent osteoclastogenesis. Gα_s variants are reliably demonstrated in osteoprogenitors, however involvement in other skeletal cell types is not well-characterized. We evaluated human specimens to investigate Gα_s variant expression in chondrocytes and osteoclasts, two prominent cell types in FD lesions. Seven of 20 bone specimens had cartilage present in addition to typical fibrous tissue. Droplet digital polymerase chain reaction detected variant Gα_s DNA in all cartilaginous samples and most fibrous tissue, in similar proportions. Variant-specific staining of Gα_s mRNA using BaseScope demonstrated variant expression in approximately 14% of chondrocytes. Approximately 3.4% of osteoclasts expressed variants, below the 5% assay false positivity rate. To further investigate this surprising finding, primary murine osteoclast cultures were treated with dibutyryl-cAMP to mimic Gα_s activation. Treatment attenuated osteoclastogenesis, diminished resorption, and toxic at high doses. To further investigate the lack of osteoclast variant expression, we isolated pre-osteoclastic monocytes from patient whole blood samples. Monocytes demonstrated an average variant allele frequency of ∼20%, with strong correlations to overall FD burden. We demonstrate that chondrogenesis is common in FD and arises directly from Gα_s variants. While osteoclasts play a pivotal role in FD pathogenesis, our results surprisingly indicate that direct expression of Gα_s variants may impair osteoclastogenesis. This study provides key insights into FD as a complex disorder driven by interplay of multiple cellular lineages and will inform development of targeted therapies.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117792"},"PeriodicalIF":3.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temporal transcriptomic profiling of bone autograft healing reveals dynamic immune, vascular, and osteogenic programs","authors":"Jared A. Mereness ,&nbsp;Sayantani Basu ,&nbsp;Lauren Benoodt ,&nbsp;Danielle S.W. Benoit","doi":"10.1016/j.bone.2025.117771","DOIUrl":"10.1016/j.bone.2025.117771","url":null,"abstract":"<div><div>Bone autograft healing is a highly orchestrated process that integrates immune activation, vascular ingrowth, and osteogenic remodeling. To define the molecular and cellular programs driving early autograft integration, bulk and single-cell RNA sequencing was used to analyze graft-associated tissues over 14 days in a murine periosteal-mediated autograft model. Global transcriptomic analysis revealed rapid and dynamic remodeling, with maximal gene expression changes occurring within the first week. The first 48 h were dominated by pro-inflammatory signaling, including TNF, IL-1, TLR, and MAPK pathways, accompanied by transcriptional signatures of phagocytosis and cellular clearance. These early inflammatory programs gave way to pro-regenerative signals, including activation of HIF-1, PI3K-AKT, Wnt, and BMP pathways, coincident with angiogenesis, osteogenesis, and matrix deposition. By day 14, extracellular matrix production and remodeling predominated, marked by metalloproteinase activity and structural matrix gene enrichment. Single-cell RNA sequencing revealed that donor-derived (eGFP⁺) graft cells were rare and transient, whereas host-derived immune cells were progressively replaced by myofibroblasts, endothelial cells, and neurogenic cell types, including GABAergic neurons and IGSF21⁺ dendritic cells, suggesting active neurovascular crosstalk during healing. Together, these data define a temporal immune-to-regenerative cascade in bone autograft repair and highlight candidate cellular and molecular targets to enhance graft performance.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"205 ","pages":"Article 117771"},"PeriodicalIF":3.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145890634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}