Journal of Bone and Mineral Research最新文献

{"title":"Deciphering the development of synovial joints in the limbs: Recent discoveries and clinical implications.","authors":"Maurizio Pacifici, Eiki Koyama, Danielle Rux","doi":"10.1093/jbmr/zjag130","DOIUrl":"10.1093/jbmr/zjag130","url":null,"abstract":"<p><p>The synovial joints are essential for skeletal function and dexterity and do so by virtue of their components and structure. The capsule protects and insulates the joint from the surrounding environment, articular cartilage provides mechanical resilience and endurance, the ligaments stabilize motion, and the synovial cavity and fluid sustain frictionless sliding. These and other fundamental aspects of synovial joint biology are well known and recognized. However, how the joints form during embryogenesis and acquire their components and functional attributes remains unclear. Happily, the last few years of research have provided new insights into limb joint development. In particular, new light has been shed on: morphogenetic mechanisms establishing the mesenchymal interzone which is the cradle of joint tissue progenitors; spatio-temporal processes endowing the joint progenitors with distinct developmental and tissue forming potentials; osmoregulatory and hydraulic forces set by Na/K-ATPase ion pumps that bring about joint cavitation and fluid accrual; cellular and signaling mechanisms establishing articular cartilage's zonal organization; and potentials of embryonically-derived progenitors residing in adult joints to engage in repair. This review describes and comments on those new studies, frames them within the broader field of joint research, and identifies lingering questions. Clinically, the treatment of joint disease remains ineffective and new directions and strategies are needed to move forward. Studies on synovial joint development are poised to provide such new directions and bring about future regenerative tools based on principles and mechanisms of developmental biology. This review is meant to highlight the potentials of such basic-to- translational-to-clinical strategies and provides an overall framework for research goals ahead.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849540","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":"Lesion Expansion in Craniofacial Fibrous Dysplasia: Natural History and Indicators of Progression in the Frontal, Zygomatic, and Sphenoid Bones.","authors":"Jonathan E Freeman, Ibrahim I Elbashir, Kristen S Pan, Vivian MacDonald, Alison M Boyce","doi":"10.1093/jbmr/zjag128","DOIUrl":"https://doi.org/10.1093/jbmr/zjag128","url":null,"abstract":"<p><p>Fibrous dysplasia (FD) is characterized by expansile fibro-osseous lesions that may occur in association with endocrinopathies as part of McCune-Albright syndrome (MAS). Craniofacial FD may result in substantial morbidity, including facial asymmetry and compression of vital neurovascular structures. There is a critical need to understand the natural history and risk factors for craniofacial lesion expansion to develop preventative trials and identify candidates for intervention. The purpose of this study was to evaluate expansion rates in periorbital bones (frontal, zygomatic, and sphenoid). Patients with craniofacial FD and serial CT imaging were evaluated. Volumetric analyses were performed and generalized mixed model analysis was used to investigate risk factors associated with expansion. Age, MAS-associated endocrinopathies, sex, Skeletal Burden Score, and history of bisphosphonate treatment were evaluated. A previous dataset for the gnathic region was included in statistical analyses to expand upon prior findings. 238 lesions (46 frontal, 43 zygomatic, 45 sphenoid, 41 mandible, 63 maxilla) in 70 patients were evaluated. Frontal, zygomatic, and sphenoid lesion volume increased with age (p<0.001), however expansion rates decreased over time (p<0.001). Both age-related expansion and lesion growth deceleration were highly location dependent, with frontal lesions experiencing the most rapid changes compared to other regions. Patients with growth hormone excess demonstrated greater lesion expansion rates (p=0.0173). There were no associations between sex and other MAS-associated endocrinopathies, or bisphosphonate treatment. Craniofacial lesion expansion rates are most rapid in younger children (generally below age 10) and decline as patients approach adulthood. FD lesions involving the frontal bone expand at a greater rate than sphenoid, zygomatic, and previously- reported gnathic lesions. These differences in growth rates indicate that location-specific analyses are critical to assess FD progression. The availability of quantitative natural history data will guide clinicians in identifying candidates for interventions, and will inform the development of clinical trials for preventative therapies.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148816871","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":"Genotype-First Characterization of Familial Hypocalciuric Hypercalcemia Type 1: Prevalence, Serum Calcium and Clinical Associations.","authors":"Nipith Charoenngam, Alicia Huerta-Chagoya, Sarah Hsu, Maheak Vora, Josep M Mercader, Miriam S Udler, Michael Mannstadt","doi":"10.1093/jbmr/zjag129","DOIUrl":"https://doi.org/10.1093/jbmr/zjag129","url":null,"abstract":"<p><p>Familial hypocalciuric hypercalcemia type 1 (FHH1), caused by inactivating CASR variants, is characterized by lifelong hypercalcemia and hypocalciuria and should be distinguished from primary hyperparathyroidism as their management differs substantially. Prior reports suggest additional clinical associations (e.g., pancreatitis, altered glucose metabolism), but epidemiological evidence is limited. Using a genotype-first analysis of UK Biobank (UKB) whole-exome/whole-genome sequencing data linked to health records, we estimated the prevalence of FHH1 and characterized its degree of hypercalcemia and clinical associations. Candidate variants were identified from the CASRdb database, which aggregates CASR variants reported in the literature and ClinVar/LOVD, and were supplemented with additional predicted high-impact variants. Variants were classified as FHH1-associated if designated in ClinVar as pathogenic/likely pathogenic (P/LP) or, for non-P/LP variants, determined to have high probability of causing FHH1 based on criteria that considered variant type, allele frequency and carrier serum calcium. We compared serum biochemistry with the remaining UKB population and performed PheWAS across ICD-10 diagnoses. Among 454,787 exomes/490,640 genomes, we identified 162 individuals carrying FHH1-associated variants (33.0/100,000). Mean serum calcium was higher in FHH1 than in the remaining UKB population (10.4±0.6 vs 9.5±0.4 mg/dL; p=1.2×10-72) but overlapped from approximately 9.2-9.4 mg/dL upward. PheWAS signals were dominated by calcium/parathyroid-related traits; pancreatitis- or diabetes-related outcomes did not meet multiple-testing-corrected significance thresholds. Serum phosphorus was modestly lower in FHH1 individuals (3.3±0.5 vs 3.6±0.5 mg/dL; p=6.7×10-17). To estimate FHH1 prevalence based on allele frequency, we used gnomAD v4.1 and found that the prevalence (SE) was 31.2(2.0)/100,000 overall and varied by ancestry, ranging from 46.6(12.5)/100,000 in the Admixed American group to 13.5(9.6)/100,000 in the Ashkenazi Jewish group. Taken together, these data indicate that FHH1 is more common than previously appreciated and is characterized by variable degrees of hypercalcemia and modest hypophosphatemia, although biochemical characterization was limited by unavailable urinary calcium and parathyroid hormone data.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148816885","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":"Identification of a novel small-molecule modulator targeting SNX10 to inhibit osteoclastic bone resorption.","authors":"Yihe Li, Qihang Wu, Shengnan Qin, Ruth Seeber, Benjamin H Mullin, Ariela Samantha, Hui Li, Ke Liu, Jie Fan, Kai Chen, Scott G Wilson, Alice Vrielink, Haiming Jin, Jiake Xu","doi":"10.1093/jbmr/zjag126","DOIUrl":"https://doi.org/10.1093/jbmr/zjag126","url":null,"abstract":"<p><p>Current antiresorptive therapies reduce bone loss by eliminating osteoclasts or inhibiting their formation. However, these approaches could disrupt osteoclast-osteoblast communication and cause serious complications with long-term usage. There is a need for developing new therapies that selectively inhibit resorptive function, while preserving osteoclast-mediated coupling effects to osteoblasts. Sorting nexin 10 (SNX10), an autosomal recessive osteopetrosis (ARO)-associated gene, plays a role mainly in osteoclast bone resorptive function. However, its potential as a target for developing therapeutic agents for bone disorders remains unexplored. In this study, we employed a multi-step approach combining artificial intelligence (AI)-driven virtual screening with high-throughput screening methods and functional assays to identify small molecules targeting SNX10 that inhibit bone resorption without impairing osteoclast formation. Our lead compound AW-006 emerged as the top candidate across all validation methods, selectively inhibiting osteoclast resorptive function while maintaining normal osteoclastogenesis in vitro. Mechanistic analyses indicated that AW-006 interacts with SNX10 and reduces its thermal stability, while molecular docking predicted binding within the PI(3)P-binding pocket and associated conformational changes affecting residues involved in PI(3)P binding and structural integrity. We discovered that SNX10 interacts with the key vesicular trafficking regulator Rab7 in living cells, and AW-006 abnormally enhances this interaction, dysregulating normal podosome belt formation in osteoclasts. Furthermore, the compound's anti-resorptive efficacy was validated in ovariectomized mice, demonstrating its therapeutic potential in estrogen deficiency-induced bone loss. Our study identifies AW-006 as a novel anti-resorptive candidate and highlights SNX10 as a promising therapeutic target for bone disorders.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786281","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":"Multimorbidity Double Burden: Elevated Refracture Risk Despite High Mortality Following Fractures - A Linked Cohort Study.","authors":"Mike Lin, Thach Tran, Dima Alajlouni, Weiwen Chen, Angela Sheu, Robert D Blank, Dana Bliuc, Jacqueline R Center","doi":"10.1093/jbmr/zjag124","DOIUrl":"https://doi.org/10.1093/jbmr/zjag124","url":null,"abstract":"<p><p>Multimorbidity - defined as the presence of two or more chronic conditions - is highly prevalent among older adults with fractures and is associated with excess mortality; however, its impact on refracture risk remains uncertain. This study aimed to quantify refracture risk across different multimorbidity clusters and fracture sites, in order to identify high-risk individuals. A whole-of-population data linkage cohort study was conducted among adults aged 50 years and above living in New South Wales, Australia with at least one hospital or emergency admission between 1 January 2005 and 30 June 2022. Individuals who sustained a fracture between 1 January 2005 to 30 June 2021 were followed until 30 June 2022 for refracture and mortality outcomes. Latent class analysis (LCA) identified multimorbidity clusters. Fine-Gray subdistribution and Cox proportional hazards models estimated refracture and mortality risk. Among 335,308 individuals with fractures, 31.2% were men (mean [SD] age, 76.3 (10.7) years) and 68.8% were women (77.4 [10.7] years). Six clusters were identified: five multimorbidity clusters (cardiometabolic, cardiovascular, cancer, geriatric and mental health; median comorbidity count: 4-13) and one low multimorbidity cluster (median comorbidity count: 0). When compared to the general NSW population risk of incident fracture and death, all clusters demonstrated substantially higher refracture risk (HR range: 2.39-3.38 in men, 1.62-2.36 in women) despite high competing mortality (HR range: 1.58-4.52 in men, 1.13-3.08 in women). The mental health cluster carried the highest refracture burden, while distal fracture sites were associated with higher refracture risk due to lower mortality. Multimorbidity does not attenuate refracture risk; instead, it heightens vulnerability among older fracture patients, even in the presence of competing mortality. These findings reinforce the need for timely, targeted secondary fracture prevention, particularly following non-hip, non-vertebral fractures.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786290","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":"Osteosarcopenia Revisited: From Mechanisms to Management.","authors":"Takayoshi Sasako, Miguel Germán Borda, Marc Sim, Gustavo Duque","doi":"10.1093/jbmr/zjag127","DOIUrl":"https://doi.org/10.1093/jbmr/zjag127","url":null,"abstract":"<p><p>Sarcopenia and osteoporosis are characterized by insufficient mass and function of skeletal muscle and bone, and often co-occur in older persons, a condition called osteosarcopenia. Loss of bone and skeletal muscle mass and function is driven by multiple risk factors that activate the hallmarks of aging. Recent genome-wide association studies in humans and animal models suggest pivotal roles for mitochondria, the nucleus, and nutrient anabolism, which are closely associated with the hallmarks of aging, as well as for osteokines and myokines, in the development of osteosarcopenia. Osteosarcopenia is associated with a higher risk of adverse outcomes, such as falls, fractures, depression, and frailty, and consequently with mortality. Diagnosis of osteosarcopenia involves various imaging techniques to assess bone mineral density and skeletal muscle mass, as well as assessments of physical performance or muscle function. Moreover, a comprehensive evaluation of medical history, medications, and laboratory data is important for identifying potential contributing factors and assessing risk. To manage and treat osteosarcopenia, a multimodal approach, such as exercise therapy, nutritional supplementation, and pharmacotherapies, is required. Future prospects include technological innovations such as artificial intelligence and the identification of novel biomarkers based on multi-omics analyses, which will help enhance early detection of this condition. Emerging drugs that positively regulate bone and muscle mass are under development and are expected to contribute to individually optimized care for osteosarcopenia.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786309","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":"Imaging and its role in predicting osteoarthritis progression Commentary on: the clinical utility of imaging in osteoarthritis and its importance in future prediction of total hip replacement; a nested case-control study within the AGES-Reykjavik cohort.","authors":"Polly Taylor, Benjamin G Faber","doi":"10.1093/jbmr/zjag041","DOIUrl":"10.1093/jbmr/zjag041","url":null,"abstract":"","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"909-910"},"PeriodicalIF":6.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281597","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":"Decreased nonvertebral fracture incidence with zoledronate use for >3 years: post hoc analysis of a Randomized Controlled Trial.","authors":"Ian R Reid, Anne M Horne, Borislav Mihov, Sonja Bastin, Mark J Bolland, Gregory D Gamble","doi":"10.1093/jbmr/zjag012","DOIUrl":"10.1093/jbmr/zjag012","url":null,"abstract":"<p><p>The anti-fracture efficacy of most osteoporosis drugs is assessed in trials of up to 3 yr duration. However, treatment of osteoporosis is required long-term, so it is important to know whether effectiveness of treatment changes over time. To date, this information has only been available from open extensions of the treatment groups from clinical trials. Such data are subject to selective loss of frailer patients from the cohort, and no placebo comparator group is available to permit reliable measurement of anti-fracture efficacy. The 6-yr Auckland zoledronate RCT administered zoledronate or placebo every 18 mo to 2000 osteopenic women aged >65 yr. It is longer than most osteoporosis trials, and only 3.6% of participants withdrew or were lost to follow-up. Therefore, anti-fracture efficacy can be validly compared between the first and second halves of this study. There were 178 non-vertebral fractures in the placebo group and 108 in the zoledronate group (excluding fractures of the hands, feet, and face). Fracture rates per 1000 women-years in the placebo group were 28 (95% CI 23, 35) and 32 (26, 40) in years 1-3 and years 4-6, respectively. In the zoledronate group, fracture rates were 23 (18, 30) and 13 (9, 18) per 1000 women-years in the first and second halves of the study. The rate ratios for non-vertebral fractures were 0.83 (0.60, 1.14) in years 1-3, and 0.40 (0.27, 0.58) in years 4-6 (between-period comparison, p < .05). Rate ratios for total fragility fractures, which include vertebral fractures also, showed a similar pattern: years 1-3, 0.76 (0.56, 1.02) and years 4-6, 0.39 (0.29, 0.53). These findings suggest that the efficacy for non-vertebral fracture prevention of anti-resorptive drugs has been underestimated because of the short-term evaluation of their effects. Further, it indicates that longer term treatment with these drugs may yield greater benefit to patients.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"945-950"},"PeriodicalIF":6.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13525198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016654","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":"Mechanisms underlying the waning of osteoanabolic therapy effects in osteoporosis.","authors":"Serge Ferrari, Cyril Thouverey, Maude Gerbaix","doi":"10.1093/jbmr/zjag053","DOIUrl":"10.1093/jbmr/zjag053","url":null,"abstract":"<p><p>Osteoanabolic therapies such as parathyroid hormone (PTH) analogs (teriparatide [TPT], abaloparatide [ABL]) and the sclerostin inhibitor romosozumab rapidly stimulate new bone deposition but their bone-building effects are not indefinite. Clinical trials including bone turnover markers and bone histomorphometry studies show that the initial gains in bone formation and density wane with continued therapy-typically within 12-18 mo for PTH analogs and even sooner for romosozumab. This invited review explores the biological mechanisms that may explain this waning response, including receptor desensitization at the PTH1 receptor level, depletion or saturation of bone-forming surfaces, exhaustion or downregulation of osteoblast progenitors, upregulation of endogenous Wnt pathway antagonists (eg, sclerostin, DKK1), and mechanostatic feedback from increased bone mass. The contrasting kinetics of TPT, ABL, and romosozumab are compared, highlighting how their modes of action (remodeling- vs modeling-based formation) influence the duration of anabolic activity. Finally, potential strategies to extend or rekindle anabolic effects are discussed-including sequential and combination therapies and adjunctive mechanical loading-with a view toward maximizing bone gains and reducing fracture risk. Understanding why anabolic drug efficacy attenuates provides insight into bone biology and guides the design of regimens to achieve more sustained increases in bone mass and strength.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"915-921"},"PeriodicalIF":6.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13525199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147497000","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":"Different Lrp5-HBM mutations induce magnitude- and surface-selective effects that are not explained by receptor trafficking.","authors":"Kyung-Eun Lim, Whitney A Bullock, April M Hoggatt, Daniel J Horan, Kyung-Shin Kang, Matthew L Warman, Alexander G Robling","doi":"10.1093/jbmr/zjag027","DOIUrl":"10.1093/jbmr/zjag027","url":null,"abstract":"<p><p>The Wnt co-receptor LRP5 plays a crucial role in skeletal physiology. Homozygous loss-of-function mutations in the Lrp5 gene produce severe osteopenia, whereas certain heterozygous point mutations produce extreme high bone mass (HBM). Different HBM-causing missense mutations are associated with variable effect magnitudes and sites of action in the skeleton. It is currently unknown whether the inclusion of 2 different HBM-causing mutations (eg, p.G171V and p.A214V), moved into the same genome, would potentiate bone mass beyond either mutation alone by manifesting their individual and divergent osteoanabolic effects. Further, a proposed unique HBM-causing mechanism of action for the G171V receptor was tested, which has poor plasma membrane localization and enriched intracellular presence. Conditional Lrp5-G171V and Lrp5-A214V were crossed to conditional mice deficient in the Wntless (Wls) gene; these mice are severely osteopenic and have impaired Wnt secretion but normal levels of intracellular (pre-released) Wnt. We tested whether the G171V mutation (which promotes intracellular localization of the receptor) would improve the skeletal phenotype induced by Wls deficiency, whereas the A214V mutation (which exhibits WT levels of plasma membrane localization) would not. The results suggest that the presence of both HBM mutations (Lrp5G171V/A214V) does not confer additional benefits to skeletal properties beyond the homozygous presence of individual HBM-causing receptors (Lrp5G171V/G171V or Lrp5A214V/A214V). Further, the severe osteopenia induced by Wls loss in bone was not affected by co-expression of the G171V mutant receptor, suggesting that intracellular retention of the G171V mutant receptor is unlikely to be the mechanism of enhanced skeletal properties in G171V mice and patients. The global knock-in studies suggest that therapeutic strategies aimed at mimicking the conformational changes in the LRP5 receptor should model the A214V (alone) rather than G171V mutations for maximizing fracture resistance. Further, the conditional studies indicate that the conundrum of G171V's ability to produce an HBM phenotype, despite very low plasma membrane expression/abundance, remains elusive.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1012-1026"},"PeriodicalIF":6.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147866187","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}