Journal of Bone and Mineral Research最新文献

{"title":"Tgif1-deficiency impairs osteoclast differentiation through PP2A-mediated ERK1/2 dephosphorylation and attenuates bone loss in mice.","authors":"Miki Maeda, Hiroaki Saito, Amy B P Ribet, Eric Hesse, Hanna Taipaleenmäki","doi":"10.1093/jbmr/zjaf107","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf107","url":null,"abstract":"<p><p>Bone remodeling is a dynamic process regulated by the activities of osteoclasts and osteoblasts. Imbalances in this process can lead to osteoporosis, a condition characterized by low bone mass and increased fracture risk. The homeodomain protein TG-interacting factor 1 (Tgif1) has been previously identified as a key regulator of osteoblast function. Here, we investigate the cell-autonomous role of Tgif1 in osteoclasts. Our findings reveal that Tgif1 is expressed in osteoclast precursors, with its expression increasing during RANKL and M-CSF-induced differentiation. Deletion of Tgif1 in the osteoclast lineage impairs osteoclast differentiation and resorption capacity, reducing aging-related bone loss in mice in vivo. Mechanistically, Tgif1 restricts ERK1/2 dephosphorylation by suppressing protein phosphatase 2A (PP2A), an ERK1/2 phosphatase. Inhibition of PP2A restores impaired differentiation of Tgif1-deficient osteoclasts, confirming its involvement in this process. These findings establish Tgif1 as an important regulator of osteoclast differentiation, function, and bone resorption, offering new insights into molecular mechanisms controlling bone mass maintenance.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854081","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":"Gut Microbiome in early life and Bone Health Outcomes at Age 6: a Danish Mother-Child Cohort Study.","authors":"Pantalius Nji Che, Jie Jiang, Monique Breslin, Michael Thompson, Rebecca K Vinding, Jakob Stokholm, Lieke E J M Scheepers","doi":"10.1093/jbmr/zjaf108","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf108","url":null,"abstract":"<p><p>The gut microbiome is associated with bone mass acquisition, yet evidence in childhood remains limited. Given that lower peak bone mass predicts osteoporosis in later life, understanding early influences is important. This analysis explores the association between the early life gut microbiome and bone health in later childhood. Data was obtained from 700 children recruited in pregnancy and followed prospectively within the Copenhagen Prospective Studies on Asthma in Childhood2010 cohort, a population-based mother-child cohort. The infant gut microbiome was measured at 1 wk (n = 445), 1 mo (n = 492), 1 yr (n = 508), 4 yr (n = 350), and 6 yr (n = 327) of age by 16S ribosomal ribonucleic acid amplicon sequencing targeting the fourth variable region. Total body less head bone mineral density and area-adjusted bone mineral content were measured by dual-energy X-ray absorptiometry at 6 yr of age. Associations were investigated by multiple linear regression, permutational analysis of variance, differential abundance analysis, and Random Forest machine learning. There were few associations between the early-life gut microbiome and bone health outcomes at age six. We found negative associations between alpha (within-sample) diversity and area-adjusted bone mineral content at 4 yr. Beta (between-sample) diversity of the gut microbiome at 6 yr was associated with concurrent bone mineral density. Escherichia-Shigella abundance at 1 mo of age associated with lower bone mineral density. Sutterella abundance at 1 yr was associated with lower bone mineral density and area-adjusted bone mineral content at 6 yr. There were no other associations between the gut microbiome and bone outcome measures at any time point. In a well-powered unselected cohort study with longitudinal sampling of the gut microbiome, there were some suggestive but no consistent associations between the early gut microbiome and bone health outcomes at 6 yr of age.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Risk of Fracture Among Women Starting Selective Serotonin Reuptake Inhibitors.","authors":"Daniel H Solomon, Kristine M Ruppert, Pam Lian, Genevieve Neal-Perry, Jane A Cauley, Sherri-Ann M Burnett-Bowie","doi":"10.1093/jbmr/zjaf106","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf106","url":null,"abstract":"<p><p>Increased fracture risk has been reported in patients using selective serotonin reuptake inhibitors (SSRIs). However, prior studies have had limited information regarding bone mineral density (BMD) and symptoms of depression, both potentially important confounders. We examined a longitudinal cohort of women who initiated SSRIs, other anti-depressant (AD) medications, or no AD to estimate the risk of fracture associated with start of SSRIs. The Study of Women's Health Across the Nation (SWAN) is a longitudinal cohort of diverse women from across the US transitioning across the menopause. Study visits are approximately yearly, with reporting of medication use, fracture incidence (any and non-traumatic), mental health scales (CES-D), and BMD (the latter occurring in selected SWAN sites). We estimated fracture incidence and relative risk among women starting SSRIs or other AD, and compared them with women not starting SSRIs or other AD. Multivariable Cox regression models with increasing adjustment were constructed. As well, secondary analyses focused on non-traumatic fractures and women with BMD measurements. SWAN includes 3,302 total women, of which 286 were excluded because of prevalent antidepressant use and 1,167 because they did not have adequate follow-up time, had a fracture prior to start of an AD, or could not be matched; this left 1,849 women for analysis. The incidence rates for any fracture (per 100 person-years) for SSRI users was 2.64 (95% CI 1.82 - 3.71), other AD users 0.80 (95% CI 0.22 - 2.04), and non-users 1.21 (95% CI 1.07 - 1.36). Fully adjusted regression models found an increased hazard ratio for any fracture among women starting SSRIs compared with no AD (HR 1.77, 95% CI 1.15 - 2.74). These results were consistent for non-traumatic fractures and in subgroups with BMD included as a covariate. Initiation of SSRI among women in mid-life was associated with an increased risk of fracture.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774386","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":"Plasma fatty acid composition predicts bone mineral accrual from childhood to adolescence: the PANIC study.","authors":"Timo A Lakka, Saara Heinonen, Taisa Sallinen, Aino-Maija Eloranta, Suvi Laamanen, Annie M Skinner, Eero A Haapala, Dimitris Vlachopoulos, Alan R Barker, Toni Rikkonen, Tomi P Laitinen, Jyrki Ågren, Sonja Soininen","doi":"10.1093/jbmr/zjaf104","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf104","url":null,"abstract":"<p><p>Little is known about the associations of plasma fatty acids with bone mineral accrual, and the evidence is mostly based on cross-sectional data. In this observational study, we investigated for the first time the longitudinal associations of plasma fatty acid composition as well as desaturase and elongase enzyme activities with bone mineral density (BMD) from childhood to adolescence. Altogether, 480 children (227 girls) aged 7-9 yr attending baseline examinations were included in the current analyses. The longitudinal associations of the proportions of fatty acids in plasma phospholipids, analyzed by gas chromatography, as well as estimated desaturase and elongase activities with total body less head BMD, measured by dual-energy X-ray absorptiometry, were analyzed by linear mixed-effects models using values from baseline, 2-yr, and 8-yr follow-up and adjusted for sex, maturity offset, follow-up time, and lean mass or fat mass. Decreased proportion of linoleic acid (standardized regression coefficient β = -.023, p = .001), increased proportion of dihomo-gamma-linolenic acid (β = .029, p < .001), and Δ6-desaturase activity (β = .032, p < .001) were associated with increased BMD independent of sex, maturity offset, follow-up time, lean mass, and fat mass. Increased proportions of nervonic acid (β = .018, p = .012), arachidonic acid (β = .019, p = .017), and docosapentaenoic acid (β = .020, p = .013) were associated with increased BMD, and these associations were partly explained by lean mass. Increased proportions of arachidic acid (β = .022, p = .005), behenic acid (β = .018, p = .010), lignoceric acid (β = .015, p = .040), and palmitoleic acid (β = .016, p = .013), increased stearoyl-CoA-desaturase activity (β = .017, p = .009), and decreased elongase activity (β = -.017, p = .023) were associated with increased BMD, and these associations were partly explained by fat mass. Single plasma saturated, monounsaturated, and polyunsaturated fatty acids have divergent longitudinal associations with BMD from childhood to adolescence. Plasma fatty acid composition predicts bone mineral accrual from childhood to adolescence, implying that fatty acid metabolism is important for healthy bone development since childhood.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758812","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":"Site-specific alterations of bone matrix mineralization, micro-hardness, and density of mineralized osteocyte lacunae in men with alcohol-associated liver disease: implications for vertebral fracture predilection.","authors":"Jelena Jadzic, Christine Plumeyer, Danica Djukic, Vladimir Zivkovic, Slobodan Nikolic, Annegreet Vlug, Nada Tomanovic, Marija Djuric, Petar Milovanovic, Björn Busse, Danijela Djonic","doi":"10.1093/jbmr/zjaf065","DOIUrl":"10.1093/jbmr/zjaf065","url":null,"abstract":"<p><p>Low bone quality has been reported as a source of bone fragility in individuals with alcohol-associated liver disease (AALD). Alterations of the bone matrix, including the spatial BMD distribution and osteocyte lacunar network characteristics, have not been comprehensively assessed in common fracture sites of individuals with AALD. Considering the clinical relevance of vertebral and femoral fragility fractures among these individuals, this cross-sectional study aimed to analyze site-specific BMD distribution, bone mechanical properties, osteocyte lacunar network, and Haversian system characteristics in the first lumbar vertebra and superolateral femoral neck of adult male donors with AALD. Quantitative backscattered electron imaging and Vickers micro-indentation testing were conducted to analyze bone quality in specimens from vertebral and femoral bone harvested at autopsy from adult male donors (n = 24), divided into 2 groups: AALD group (12 individuals with histopathological confirmation of AALD, age: 60 ± 12 yr) and age-matched controls (12 individuals without histopathological features of liver disease, age: 59 ± 12 yr). The comparative assessment revealed significantly lower mean calcium content, reduced Vickers micro-hardness, higher density of osteocyte lacunae occluded with mineralized matter (ie, micropetrosis), thicker osteonal wall, and a higher percentage of osteon refilling in lumbar vertebrae and superolateral femoral neck obtained from the AALD group (p < .05). Although bone quality alterations were congruent in both skeletal sites, the most severe AALD-induced impairment was noted in the trabecular compartment of lumbar vertebrae (p < .05). Our findings revealed a site-specific reduction in trabecular bone mineralization and an increased proportion of mineralized osteocyte lacunae in male individuals with AALD, which may contribute to increased vertebral predilection in these individuals.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"987-998"},"PeriodicalIF":5.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232785","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":"Real-world effectiveness of burosumab vs oral phosphate and active vitamin D in adults with X-linked hypophosphatemia.","authors":"Pablo Florenzano, Erik A Imel, Aliya A Khan, Zhiyi Li, Marc Vincent, Takanobu Nomura, Stanley Krolczyk, Ben Johnson, Leanne Ward","doi":"10.1093/jbmr/zjaf063","DOIUrl":"10.1093/jbmr/zjaf063","url":null,"abstract":"<p><p>In X-linked hypophosphatemia (XLH), PHEX gene variants lead to elevated FGF23 production, resulting in hypophosphatemia, osteomalacia, osteomalacia-related fractures, osteoarthritis, enthesopathy, spinal stenosis, and symptoms of pain, stiffness, and decreased physical function. Burosumab is an anti-FGF23 monoclonal Ab approved for XLH treatment. Randomized studies comparing oral phosphate/active vitamin D (Pi/D) to burosumab in adults are lacking. This analysis, which utilized real-world data from the prospective, Americas-based XLH Disease Monitoring Program (NCT03651505), evaluated the effectiveness of burosumab vs Pi/D, based on changes from baseline to the year 1 visit in serum phosphate, 1,25(OH)2D, PTH, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS PF), and Timed Up and Go performance outcome. Two cohorts of adults with XLH who either began burosumab between baseline and the year 1 visit (n = 65) or were on Pi/D (n = 74) at study entry and did not receive burosumab were included. Inverse probability of treatment weighting was employed to adjust for potential confounding due to baseline cohort differences. At the year 1 visit, mean (SE) change from baseline was significant for burosumab vs Pi/D in serum phosphate (0.78 [0.08] vs 0.15 [0.14] mg/dL; p < .001), 1,25(OH)2D (19.41 [3.39] vs 5.49 [3.43] pg/mL; p = .011), PTH (-13.82 [5.00] vs 11.79 [8.10] pg/mL; p = .006), WOMAC pain (-7.50 [2.34] vs 4.47 [3.23]; p = .004), WOMAC physical function (-5.68 [1.96] vs 6.77 [4.85]; p = .006), and WOMAC total (-7.78 [2.06] vs 3.15 [3.37]; p = .005) scores, PROMIS PF (1.51 [0.73] vs -1.64 [1.11], p = .018), and TUG (-1.19 [0.42] vs 0.55 [0.43] s, p = .011). A trend towards improved WOMAC stiffness was observed for burosumab (-10.16 [2.85] vs -1.79 [3.68]; p = .086). In this real-world analysis of adults with XLH, burosumab treatment was associated with improved biochemical parameters, pain, physical function, and mobility compared with Pi/D.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"973-986"},"PeriodicalIF":5.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12308825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959445","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":"Taking a closer look at matrix vesicle biogenesis.","authors":"Charlotte Clews, Scott Dillon, Fabio Nudelman, Colin Farquharson, Louise A Stephen","doi":"10.1093/jbmr/zjaf076","DOIUrl":"10.1093/jbmr/zjaf076","url":null,"abstract":"<p><p>Matrix vesicles (MVs) are crucial components in the development of a healthy mineralized skeleton. They are also the key elements leading to the pathological calcification of vasculature; however, we know surprisingly little about them. First characterized over 55 yr ago, MVs are small membrane bound extracellular vesicles (EVs) that provide an environment for the concentration of calcium and phosphate. This makes MVs the first step in producing calcium phosphate, leading to the nucleation of HA mineral within the extracellular matrix, the key process in biomineralization. In this review, we discuss the literature on MV biogenesis and explore their components in the context of EVs and exosomes. We consider MVs in light of the Minimal Information for Studies of Extracellular Vesicles (MISEV2023). In doing so, we identify striking parallels in the biogenesis, contents, and roles of MVs and exosomes, opening opportunities for new avenues of research and understanding. We also explore the debate around whether MVs really contain HA, and propose emerging technologies, particularly in the field of imaging, to improve our understanding of MVs and galvanize research in the area over the coming years. By taking a closer look at MV biogenesis, we will be able to make use of the emerging technologies around EVs more widely, with the aim of fully understanding these vital vesicles and harnessing their potential therapeutic benefits.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"931-945"},"PeriodicalIF":5.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12308673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191310","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":"Proton pump inhibitor exposure, trabecular bone score, and BMD: a registry-based cohort study.","authors":"Fatima Zarzour, John T Schousboe, Neil Binkley, Didier Hans, William D Leslie","doi":"10.1093/jbmr/zjaf072","DOIUrl":"10.1093/jbmr/zjaf072","url":null,"abstract":"<p><p>Proton pump inhibitors (PPI) are widely prescribed medications. Proton pump inhibitors exposure may be associated with lower trabecular bone score (TBS), but has not shown a consistent effect on BMD. We hypothesized that abdominal obesity, which is associated with both gastroesophageal disease and PPI use, could confound the relationship between PPI use and TBS. We assessed the effect of PPI use on TBS (primary measurement) and BMD (secondary measurements) before and after adjustment for sagittal abdominal diameter (SAD), a DXA-derived measure of abdominal soft-tissue thickness. The study population comprised 60 930 individuals (90.3% women, mean age 65.7 yr) that included 11 340 (18.6%) with PPI use in the preceding 12 mo. PPI exposure was categorized from medication persistence ratio (MPR) as non-use (referent), minimal (MPR 0.01-0.25), mild (MPR 0.26-0.5), moderate (MPR 0.51-0.75), and high use (MPR 0.76-1). When logistic regression models were minimally adjusted for age, sex, and scanner, increasing PPI use versus non-use was associated with progressively increasing odds ratios (ORs) for TBS in the lowest tertile (minimal 1.11 [95% CI 1.02-1.22], mild 1.18 [1.04-1.34], moderate 1.34 [1.17-1.53], high 1.41 [1.31-1.52]) but inversely with osteoporotic BMD (minimal 0.97 [0.89-1.06], mild 0.85 [0.75-0.97], moderate 0.82 [0.72-0.94]), and high 0.76 [0.70-0.82]). Sagittal abdominal diameter was greater in PPI users than non-users. After further adjustment for SAD, PPI use was not associated with lower TBS or BMD. Similar patterns were seen in men and women, and for longer durations of PPI use. Among 4742 with a second DXA (mean interval 3.4 yr), PPI use was not associated with more rapid TBS or BMD loss compared to non-users. In conclusion, PPI use is associated with greater SAD, an indicator of abdominal obesity. SAD and other clinical variables have a confounding effect on TBS and BMD measurements. When fully adjusted, PPI exposure did not significantly decrease TBS or BMD.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"965-972"},"PeriodicalIF":5.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12308828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074987","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 pain in fibrous dysplasia does not rely on aberrant sensory nerve sprouting or neuroma formation.","authors":"Biagio Palmisano, Chiara Tavanti, Giorgia Farinacci, Giorgio Gosti, Marco Leonetti, Samantha Donsante, Giuseppe Giannicola, Natasha Appelman-Dijkstra, Alessandro Corsi, Ernesto Ippolito, Mara Riminucci","doi":"10.1093/jbmr/zjaf066","DOIUrl":"10.1093/jbmr/zjaf066","url":null,"abstract":"<p><p>Bone pain is a major symptom of many skeletal disorders. Fibrous dysplasia (FD) is a genetic disease with mono or polyostotic skeletal phenotype due to the post-zygotic occurrence of the causative Gsα mutation. Bone pain in FD often associates with skeletal deformities and fractures or nerve impingement by the pathological tissue. However, even in the absence of complications, FD patients often complain of a chronic pain that does not correlate with their disease burden. Multiple hypotheses have been made to explain this pain. However, its pathogenetic mechanisms remain, as yet, largely unexplored. In this study, we first demonstrate that the FD mouse model EF1α-GsαR201C develops behavioral impairments and altered response to nociceptive stimuli that, as in FD patients, do not correlate with their skeletal disease burden, thus providing a reliable model to study bone pain in FD. Then, we show that in EF1α-GsαR201C mice, the overall pattern of skeletal innervation is preserved and that within FD lesions, sensory fibers are variably and focally distributed, mainly at perivascular sites. Finally, we provide the first analysis of a series of human FD bone biopsies showing that, within the lesional tissue, sensory nerve fibers are few despite the rich vascular network and appear to be well-organized. These data show that, albeit sensory nerve fibers are found within FD lesions, bone pain in humans and functional impairment in mice are not associated to pathological sensory nerve sprouting or formation of neuromas in the Gsα-mutated skeleton.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"999-1014"},"PeriodicalIF":5.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12308826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952518","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":"Programmed cell death protein 1 (PD-1) blockade regulates skeletal remodeling in a sex- and age-dependent manner.","authors":"Gwenyth J Joseph, Lawrence A Vecchi Iii, Sasidhar Uppuganti, Jeremy F Kane, Margaret Durdan, Paige Hill, Ashtyn G McAdoo, Hidenori Tanaka, David Kell, Madeline B Searcy, Wei Chen, Eben L Rosenthal, David G Harrison, Jeffry S Nyman, Megan M Weivoda, Rachelle W Johnson","doi":"10.1093/jbmr/zjaf055","DOIUrl":"10.1093/jbmr/zjaf055","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) block immunoregulatory receptor-ligand interactions and robustly increase survival of cancer patients but frequently result in immune-related adverse events (irAEs). While rheumatologic toxicities are commonly reported as irAEs, the effect of immune checkpoint blockade on the underlying mechanisms of ICI-induced fractures and bone loss is controversial, with reports of both positive and negative effects on bone mass in preclinical models. However, no previous reports have investigated the impact of ICIs on females or aged mice, or on fracture risk in either sex. We report that global deletion of programmed cell death protein 1 (PD-1) broadly results in bone loss in skeletally mature male and female PD-1-/- mice, with a sexually divergent phenotype in adolescent mice, decreased bone strength in adult males and young females, and expansion of multiple T cell subsets in the bone marrow. In a model of pharmacologic PD-1 blockade, administration of α-PD-1 reduced bone mass, expanded multiple T cell subsets in the bone marrow, and increased osteoclast activity and resorptive capacity. T cell deficient mice were resistant to osteoclast-mediated bone loss following α-PD-1 therapy, suggesting that T cells in the bone marrow are necessary for bone loss in the setting of ICI therapy. These findings may be leveraged to identify patients at greater fracture risk following ICI therapy due to enrichment of effector T cell populations in the bone marrow.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"950-964"},"PeriodicalIF":5.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12340981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952841","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}