Journal of Bone and Mineral Research最新文献

{"title":"Longitudinal comparison of bone, growth, and biochemical markers in breastfed HIV-exposed uninfected and HIV-unexposed Ugandan children.","authors":"Florence Nabwire, Matthew M Hamill, Mary Glenn Fowler, Adeodata Kekitiinwa, Josaphat Byamugisha, Ann Prentice","doi":"10.1093/jbmr/zjag024","DOIUrl":"10.1093/jbmr/zjag024","url":null,"abstract":"<p><p>Due to successful maternal antiretroviral therapy (ART), pediatric HIV infections have declined, leading to a growing population of children HIV-exposed uninfected (CHEU) in Sub-Saharan Africa. However, studies report poorer growth and development in CHEU vs children HIV-unexposed uninfected (CHUU), raising concerns about maternal HIV and ART exposure, particularly tenofovir disoproxil fumarate (TDF). This analysis of data from the Gumba study compares growth trajectories, bone mineral accretion, and biochemical markers of growth and bone metabolism to age 18 mo in Ugandan CHEU, exposed to maternal HIV and TDF-containing ART in utero and via breastmilk (n = 85), and CHUU peers (n = 80). The groups had similar weight and length 2 wk after birth (WK2), but, despite higher exclusive breastfeeding rates, CHEU had slower growth by WK14 and ~0.5 kg lower body weight and fat mass by WK26. Growth faltering occurred in both groups from WK26, with widening differences: by WK78, 59% of CHEU were stunted compared to 33% of CHUU. Children HIV-exposed uninfected had lower whole-body (WB) BMC and bone area at WK14 and WK26 (p = .03 and .0003 for interaction, respectively), but similar WB areal BMD before and after size adjustment, indicating accrued bone mineral was appropriate for their slower growth. There were no group differences in biochemical markers of growth or bone formation. However, CHEU had higher C-terminal telopeptide (CTX), a marker of bone resorption, at WK14 (group difference (95% CI): +50.9 (24.1)%, p < .001) coinciding with higher maternal CTX concentrations, and at WK78 (+45.6 (28.9)%, p < .05). These findings suggest early onset growth deficits and altered bone metabolism in CHEU by 3 mo of age, possibly linked to the TDF-containing ART initiated during pregnancy and/or disruptions in bone metabolism observed in their mothers. Further studies are needed to investigate the mechanisms and long-term implications for growth and bone health in CHEU.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"823-836"},"PeriodicalIF":6.5,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13421069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111713","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 molecular and functional interplay between the osteopetrosis-associated proteins SNX10, OSTM1, and CLC-7 during mouse osteoclastogenesis.","authors":"Nina Reuven, Sabina Winograd-Katz, Maayan Barnea-Zohar, Amir Pri-Or, Yishai Levin, Jean Vacher, Benjamin Geiger, Ari Elson","doi":"10.1093/jbmr/zjaf196","DOIUrl":"10.1093/jbmr/zjaf196","url":null,"abstract":"<p><p>Bone-resorbing osteoclasts (OCLs) are large, multi-nucleated cells that are formed through well-regulated differentiation and cell fusion of monocyte-macrophage precursors. Abnormally increased or decreased OCL-mediated bone resorption perturbs bone structure and homeostasis and may lead to severe illnesses, such as osteoporosis and autosomal recessive osteopetrosis (ARO), respectively. Mutations in the intracellular trafficking-associated protein sorting nexin 10 (SNX10) lead to \"OCL-rich\" ARO, in which OCLs are inactive. Mature, SNX10-deficient murine OCLs fuse continuously to generate gigantic cells, in vitro and in vivo, unlike WT OCLs that stop fusing with each other upon maturation, indicating that SNX10 is required for both the resorptive activity of OCLs and the arrest of cell fusion upon maturation. Mutations in CLC-7 and OSTM1, which comprise the lysosomal voltage-gated Cl-/H+ exchanger, also induce OCL-rich ARO in humans and in mouse models, and are associated with the presence of large OCLs. In this study, we explored the molecular interplay between SNX10, CLC-7, and OSTM1 by comparing the phenotypes of cultured mouse OCLs lacking one of these proteins. We show that loss of each protein leads to the formation of similarly-gigantic OCLs in culture, due to deregulated fusion between mature OCLs that proceeds with similar kinetics. All 3 proteins co-localize in LAMP1-positive lysosomes, located at both perinuclear and peripheral regions of mature WT OCLs. SNX10-KO OCLs exhibit few peripheral lysosomes containing CLC-7 and OSTM1, indicating that SNX10 is required for regulating their trafficking to the cell periphery. CLC-7 and SNX10 physically interact with each other and loss of CLC-7 depletes peripheral OSTM1-containing lysosomes, indicating that CLC-7 is also required for this transport. Taken together, these findings indicate that SNX10 and CLC-7 regulate the subcellular distribution of lysosomes containing CLC-7 and OSTM1, thereby establishing a functional link between these 3 proteins that controls both the fusion and functionality of mature OCLs.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"859-873"},"PeriodicalIF":6.5,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13421078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145772925","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":"Sex-specific bone architectural deficits among older adults living with HIV: a cross-sectional study from Zimbabwe.","authors":"Mícheál Ó Breasail, Kate A Ward, Tadios Manyanga, Hannah Wilson, Camille Pearse, Anya Burton, Lucy Gates, Chris Grundy, Anthony Muchai Manyara, Denekew Tenaw Anley, Cynthia Kahari, Tafadzwa Madanhire, Peter R Ebeling, Rashida A Ferrand, Celia L Gregson","doi":"10.1093/jbmr/zjag082","DOIUrl":"10.1093/jbmr/zjag082","url":null,"abstract":"<p><p>People with HIV (PLWH) are living longer with antiretroviral therapy (ART) but HIV increases the risk of age-associated diseases including osteoporosis. A cross-sectional study of men and women ≥40 years was conducted in Harare, Zimbabwe. Sociodemographic data, HIV status/treatment, and anthropometry were collected. Outcomes were peripheral quantitative computed tomography (pQCT): total volumetric bone mineral density v(BMD), trabecular vBMD, cross-sectional area (CSA), compressive bone strength (BSIc), cortical vBMD, cortical thickness, proximal CSA, and polar stress-strain index (pSSI). Sex-stratified linear regression determined differences by HIV status, minimally adjusted for age and wealth-index (WI), and further adjusted for height and weight. Linear regression adjusted for age and WI assessed associations between HIV- and ART-duration, TDF-use, and viral suppression on bone. 1101 participants (PLWH 20.3%; Male 48.6%), aged mean(SD) 62.4(14.1) years, had pQCT data. HIV-related bone impairments, robust to full adjustment for age, wealth-index, height, and weight were observed. Men with HIV (MLWH) had lower radial total vBMD (-7.1% [-10.9; -3.2]%), trabecular vBMD (-11.3% [-16.9%; -5.6%]), and BSIc (-12.0% [-18.7%; -5.4]%) than HIV-negative men. Trabecular findings were similar in women with HIV (WLWH), plus lower cortical vBMD (-1.4 [-2.3; -0.6]%) and thickness (-7.2 [-11.1; -3.3]% were also seen. Tibial pQCT findings were broadly consistent. In WLWH , years since HIV-diagnosis were associated with lower radius total vBMD (-1.9% per-year [-3.2%; -0.6%]), trabecular vBMD (-4.2% [-6.5%; -2.0%]), BSIc (-3.9% [-6.2%; -1.6%]), cortical vBMD (-0.3% [-0.6%; -0.1%]), and thickness (-1.6% [-2.7%; -0.5%]). In MLWH, years since HIV-diagnosis were associated with smaller proximal tibia CSA (-1.0% [-1.9%; -0.2%]) and TDF-use with lower tibia cortical vBMD (-1.4% [-2.8%; -0.1%]). Older Zimbabwean PLWH have markedly lower trabecular vBMD compared to HIV-negative peers additional cortical compartment impairments were evident in women. These data add to the growing evidence that women with HIV in particular may be at increased risk of age-associated osteoporotic fragility fracture relatively early in their life-course.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"848-858"},"PeriodicalIF":6.5,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13421066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147925044","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":"Recovery in BMD following recent repeat pregnancy and breastfeeding among African women with and without HIV.","authors":"Flavia Matovu Kiweewa, Lara Lewis, Lynda Stranix-Chibanda, Sufia Dadabhai, Patience Atuhaire, Felluna Chauwa, Jim Aizire, Taha E Taha, John M Pettifor, Sean S Brummel, Todd T Brown, Mary Glenn Fowler","doi":"10.1093/jbmr/zjag021","DOIUrl":"10.1093/jbmr/zjag021","url":null,"abstract":"<p><p>Women living with HIV (WLWH) in resource-limited settings have benefited greatly from antiretroviral therapy (ART). However, they have several risk factors that can affect their bone health including being female, high parity/breastfeeding, use of life-long ART, and HIV disease itself. This study assessed bone mineral density (BMD) among recently pregnant WLWH (WLWH-P), and compared BMD changes over 3 yr with WLWH who were not pregnant (WLWH-NP) and with recently pregnant HIV-negative women (HIV-neg-P). We co-enrolled 104 WLWH-P from an ongoing cohort study in Malawi and Uganda, and used linear mixed models to compare standardized BMD values over 30-36 mo with 109 HIV-neg-P women matched for age-group/parity, and 99 age-group/parity matched WLWH who did not plan to become pregnant over 36 mo. BMD was assessed via DXA at baseline, 12, 24, and 30-36 mo. At baseline, median age of WLWH was 33 yr with HIV-neg-P being 32 yr. 91.4% of WLWH-P, and 87.9% of WLWH-NP were on Tenofovir-ART regimens. At baseline, 12, 24, and 30-36 mo postpartum, WLWH-P had lower mean standardized BMD values for FN, LS, and TH compared to HIV-neg-P women, although differences were not statistically significant except for baseline TH. In conclusion, both groups demonstrated BMD increase to above baseline scores by 30-36 mo. For WLWH-P compared to WLWH-NP, mean standardized BMD values trended lower between baseline and 24 mo. Both WLWH-P and HIV-neg-P women showed BMD recovery to baseline for FN, LS, and TH by 30-36 mo postpartum. However, mean BMD standard-scores trended lower throughout follow-up for WLWH-P compared to HIV-neg-P women. WLWH-P and WLWH-NP women had similar BMD standardized scores by 30-36 mo. The BMD recovery results are encouraging, but longer follow-up is needed to assess fracture risk among older WLWH compared to HIV-negative women.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"837-847"},"PeriodicalIF":6.5,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13421074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462500","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":"Accelerated osteocytic citrate production in chronic kidney disease is associated with protection of the kidney.","authors":"Jie Ren Gerald Har, Maggie Yun-Hsuan Hsu, Keith L Saum, Akshdeep Singh, Ruchir Sriram, Dylan P Kuennen, Emily K Zhu, Subramaniam Pennathur, Maciek R Antoniewicz, Lauren E Surface","doi":"10.1093/jbmr/zjag114","DOIUrl":"10.1093/jbmr/zjag114","url":null,"abstract":"<p><p>Metabolites mediate inter-organ communication and this metabolic crosstalk often goes awry in systemic diseases, including chronic kidney disease-mineral bone disorder (CKD-MBD), where CKD disrupts skeletal homeostasis, with significant bone loss and increased fracture risk observed in patients. While metabolites from the injured kidney have been identified to disrupt bone function, whether metabolites from the bone influence kidney function over the course of CKD progression is less-understood. Given that bone-derived factors such as FGF23 and sclerostin influence CKD-MBD disease progression, we hypothesized that identifying skeletal metabolic fluxes disrupted in CKD may reveal other bone-derived metabolites that mediate nephropathy. We employed a combination of in vivo and ex vivo  13C-metabolic flux analysis (13C-MFA) to characterize how the adenine-induced kidney injury murine model of CKD-MBD rewires specific skeletal metabolic fluxes. Through 13C-MFA of bone tissue in vivo, and ex vivo cultures of calvariae and femora, we identified that this murine model of CKD-MBD accelerates osteocytic citrate production. 13C-isotopic tracing in OCY454 osteocytes suggests that this increased citrate flux is in part driven by PTH stimulation of glucose- and glutamine-to-citrate conversion in osteocytes. When citrate production is exacerbated by the loss of function mutation in SLC13A5 (Slc13a5R337*/R337*), a specialized plasma membrane citrate importer, we did not observe a significant worsening of bone loss in mutant mice due to chronic adenine-induced kidney injury. Intriguingly, kidney function appears to be protected, reducing secondary hyperparathyroidism and the severity of nephrolithiasis due to the adenine diet. Our observation on the role of citrate metabolism in CKD both confirms the relevance of citrate in managing patient kidney outcomes and suggests that organismal citrate metabolism may be modulated in the management of CKD-MBD. Altogether, this study reveals a potential new axis of metabolic regulation in the inter-organ communication between the skeleton and the kidneys.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148576364","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":"Osteoarthritis risk associated with denosumab in adults with osteoporosis: A target trial emulation.","authors":"Masaki Hatano, Yuya Kimura, Akira Okada, Hisatoshi Ishikura, Takeyuki Tanaka, Taku Saito, Sakae Tanaka, Hideo Yasunaga","doi":"10.1093/jbmr/zjag113","DOIUrl":"https://doi.org/10.1093/jbmr/zjag113","url":null,"abstract":"<p><p>Denosumab, a well-established osteoporosis treatment, has demonstrated potential bone- and cartilage-protective effects in preclinical and early trials. However, it remains unclear whether these promising findings extend to osteoarthritis prevention in weight-bearing joints and broader real-world osteoporotic populations. We compared osteoarthritis incidence between denosumab and oral bisphosphonates in adults aged 50 years or older with osteoporosis using a sequential nested target trial emulation with propensity score matching based on longitudinal health insurance claims data from Japan collected between 2015 and 2024. Two target comparisons were conducted: one compared new users of denosumab with new users of oral bisphosphonates, and the other compared patients who switched from oral bisphosphonates to denosumab with those who continued oral bisphosphonates. The primary outcome was osteoarthritis incidence. Secondary outcomes included joint-specific osteoarthritis (knee, hip, and hand) over 3 years. The absolute risk reduction (ARR) and relative risk (RR) at 3 years were estimated using a Kaplan-Meier estimator in both the per-protocol and intention-to-treat analyses. In the per-protocol analyses, the ARR for incident osteoarthritis was 2.0% (95% confidence interval [CI], 1.1%-3.2%) in the new-user comparison, with an RR of 0.83 (95% CI, 0.73-0.91), and 0.9% (95% CI, -0.2% to 2.8%) in the switch-continue comparison, with an RR of 0.92 (95% CI, 0.76-1.02). In the intention-to-treat analyses, the corresponding ARR was 1.9% (95% CI, 1.3%-3.3%) in the new-user comparison, with an RR of 0.84 (95% CI, 0.73-0.89), and 1.2% (95% CI, -0.2% to 2.7%) in the switch-continue comparison, with an RR of 0.89 (95% CI, 0.77-1.02). Denosumab initiation was associated with a modestly lower risk of incident osteoarthritis than oral bisphosphonate initiation, although the association was weaker in the switch-continue comparison.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560304","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":"Postnatal deletion of Dlx5/6 in Osx-lineage cells drives bone hypertrophy by regulating osteoblast expansion and maturation.","authors":"Morgane Bourmaud, Nicolas Narboux-Neme, Mylène Zarka, Camille Blandin, Sebastien Mella, Valentina Libri, Milena Hasan, Eric Hay, Giovanni Levi, Martine Cohen-Solal","doi":"10.1093/jbmr/zjag112","DOIUrl":"https://doi.org/10.1093/jbmr/zjag112","url":null,"abstract":"<p><p>Distal-less homeobox genes Dlx5 and Dlx6 are key regulators of osteoblast differentiation during skeletal development, but their role in postnatal bone remodeling remains poorly understood. To investigate this, we conditionally deleted Dlx5/6 in Osterix-lineage cells after 4 weeks of birth using an inducible Osx-Cre system. Dlx5/6Δ/Δ Osx-Cre and control mice were analyzed in terms of bone architecture (micro-computed tomography), remodeling (histomorphometry), gene expression profiling and single-cell RNA sequencing. Postnatal deletion of Dlx5/6 induced a complex skeletal phenotype characterized by radial bone hypertrophy and altered cortical remodeling. Enhanced periosteal activity was associated with increased Osx expression in periosteal cells, confirmed by BaseScope and immunofluorescence analyses. In parallel, cortical bone became thinner and more porous, while trabecular bone displayed reduced bone formation and thinner trabeculae, despite paradoxical accumulation within the diaphysis. These alterations were associated with increased Osx expression in periosteal and diaphyseal compartments, indicating abnormal spatial regulation of osteolineage cell expansion and bone remodeling. Single-cell transcriptomic analysis in bone-marrow cells identified altered mesenchymal stromal cell populations with dysregulated extracellular matrix and Wnt signaling pathways, including downregulation of the Wnt antagonist Sfrp1, validated in situ by RNAscope. Consistently, osteoblasts derived from Dlx5/6Δ/Δ Osx-Cre displayed impaired terminal differentiation in vitro, with reduced expression of late osteogenic markers and decreased matrix mineralization. Collectively, these findings identify Dlx5/6 as critical regulators of postnatal bone homeostasis that coordinate osteolineage expansion and terminal osteoblast maturation during postnatal bone remodeling.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547104","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":"HR-pQCT measures of bone in autosomal dominant osteopetrosis highly correlate with fractures and inversely correlate with bone resorption markers.","authors":"Stuart J Warden, Erik A Imel, Ziyue Liu, Corinne Parks-Schenck, Netsanet Gebregziabher, Rita Gerard-O'Riley, Marian Hart, Lynda E Polgreen, Michael J Econs","doi":"10.1093/jbmr/zjag109","DOIUrl":"10.1093/jbmr/zjag109","url":null,"abstract":"<p><p>Autosomal dominant osteopetrosis (ADO) is a rare bone disorder caused by impaired osteoclastic resorption. Despite high bone mass, ADO is paradoxically associated with increased fracture risk. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides unique, low-radiation assessments of bone, but prior studies in ADO are limited to small case series. Using baseline cross-sectional data from an ongoing natural history study, we characterized HR-pQCT phenotypes in adults with ADO and explored associations with self-reported fracture history and bone turnover markers. HR-pQCT outcomes at the distal ends and shafts of the radius and tibia in 48 adults with ADO were compared to 144 matched controls (1, 3 ratio). In addition, z-scores for outcomes in ADO were calculated using established reference data. At trabecular-rich distal sites, ADO demonstrated markedly elevated total volumetric bone mineral density (vBMD), trabecular vBMD, trabecular bone volume fraction, trabecular thickness, and estimated failure load (all p<0.001), with values often approaching or exceeding twice those in controls. At cortical-rich shaft sites, total vBMD, bone area, bone area fraction, and cortical thickness were greater in ADO (all p<0.05). However, there was considerable interindividual variability, with some individuals having normal z-scores while others exhibited z-scores exceeding +20. The phenotype reflected increased bone mass rather than mineralization-cortical vBMD was normal and tissue mineral density was normal-to-lower in ADO. Outcomes at both distal and shaft sites were strongly correlated with lifetime fracture number (Spearman ρ=0.64-0.75, p<0.001), indicating ADO individuals with the \"strongest\" bones (via micro-finite element modeling) reported most fractures. The outcomes were correlated inversely with serum C-telopeptide and positively with serum tartrate resistant acid phosphatase 5b, consistent with ADO being rich with dysfunctional osteoclasts. Overall, the data reveal the profound, yet variable, phenotype in ADO and indicate that HR-pQCT measures correlate with disease severity and represent potential surrogate endpoints for future therapeutic trials.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417198","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":"Bone phenotype in a mouse model of Classical Ehlers Danlos syndrome with Col5a1 haploinsufficiency.","authors":"Keren Machol, Catherine G Ambrose, Deidre N Meyers, Nadja Fratzl-Zelman, Stéphane Blouin, Markus A Hartmann, Urszula Polak, Barakat Ibrahim, Duncan Crosby, Oscar E Ruiz, Brendan H Lee","doi":"10.1093/jbmr/zjag110","DOIUrl":"https://doi.org/10.1093/jbmr/zjag110","url":null,"abstract":"<p><p>Type V collagen is a key regulator in the formation of type I collagen fibrils in connective tissues including skin, tendons, and bones. Abnormalities in type V collagen cause classical Ehlers Danlos syndrome (EDS), a connective tissue disorder with primarily skin and joint phenotype. There are several clinical reports suggesting increased prevalence of vertebral fractures in adult patients with EDS, among them patients with classical EDS. Yet, the literature lacks data about bone health specifically in the classical EDS patient population. The Col5a1 haploinsufficient mouse model (Col5a1+/-) recapitulates the human disease phenotype with hyperextensible and fragile skin, delayed wound healing, and tendons with reduced tensile strength. The bone phenotype in this model is unknown. Here we present a comprehensive bone phenotyping of this model using 3-point bending, vertebral compression studies, micro computed tomography (microCT) analysis, Raman spectroscopy, and quantitative Backscattered Electron Imaging (qBEI) to test bone quantity, quality, composition, and mineralization density distribution. We found no difference in all parameters tested between Col5a1+/- and Col5a1+/+ mice 8 weeks and 6 months old in both sexes. Bulk RNA sequencing in tibiae from 8-week-old males identified only minimal changes in gene expression. Our results show that the Col5a1 haploinsufficient mouse model does not have a significant bone phenotype and suggest that individuals with heterozygote loss of function variants in COL5A1 may not have a higher risk for fractures due to primary bone abnormality.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417139","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":"Programmed cell death ligand 1 (PD-L1) inhibition in tumor naïve mice is bone-sparing throughout the lifespan.","authors":"Madeline B Searcy, Gwenyth J Joseph, Jeremy F Kane, Laasya Challa, Hidenori Tanaka, Sasidhar Uppuganti, Jailyn A Smith, Eben L Rosenthal, David G Harrison, Jeffry S Nyman, Megan M Weivoda, Rachelle W Johnson","doi":"10.1093/jbmr/zjag104","DOIUrl":"https://doi.org/10.1093/jbmr/zjag104","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) which target immune checkpoint proteins like programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have revolutionized cancer therapy. Skeletal toxicities are emerging immune-related adverse events for patients treated with ICIs, and PD-1 blockade in pre-clinical mouse models significantly reduces bone mass. However, the effect of PD-L1 inhibition on the bone throughout development is not well understood. We investigated the role of PD-L1 loss on bone microarchitecture with genetic PD-L1 knockout in myeloid cells using LysM-Cre;PD-L1Flox/Flox mice and pharmacologic inhibition with a PD-L1 neutralizing antibody in adult and aged mice. We report that neither PD-L1 deletion in myeloid cells nor inhibition with α-PD-L1 significantly impacts femoral trabecular bone microarchitecture; however, α-PD-L1 treatment increases vertebral trabecular bone volume. Additionally, PD-L1 blockade influences T cell expansion by decreasing naïve T cells and increasing effector memory T cells in the bone marrow, consistent with previous studies on the effects of PD-1 inhibition. The trabecular bone-sparing effect of PD-L1 inhibition is strikingly different from the bone loss observed with PD-1 blockade. Clinical studies are necessary and justified to determine if PD-L1 may be a less bone destructive alternative for cancer patients treated with ICIs who are at high risk of fracture.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417183","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}