Journal of Bone and Mineral Research最新文献

{"title":"Loss-of-function of DDR1 is responsible for a chondrodysplasia with multiple dislocations.","authors":"Miriam Villegas Villarroel, Céline Huber, Geneviève Baujat, Adeline Bonnard, Corinne Collet, Valérie Cormier-Daire","doi":"10.1093/jbmr/zjae205","DOIUrl":"https://doi.org/10.1093/jbmr/zjae205","url":null,"abstract":"<p><p>Chondrodysplasias with multiple dislocations are rare skeletal disorders characterized by hyperlaxity, joint dislocations, and growth retardation. Chondrodysplasias with multiple dislocations have been linked to pathogenic variants in genes encoding proteins involved in the proteoglycan biosynthesis. In this study, by exome sequencing analysis, we identified a homozygous nonsense variant (NM_001297654.2: c.1825C > T, p.Arg609*) in the discoidin domain receptor 1 (DDR1) gene in a patient presenting joint dislocations, hyperlaxity, and cerebellar hypoplasia. Functional studies revealed decreased proteoglycan production in patient fibroblasts. We further demonstrated that DDR1 inhibition impaired the Indian Hedgehog (IHH) signaling pathway in chondrocytes, decreased differentiation and mineralization in osteoblasts, and disrupted p38 MAPK signaling in both cell types. Additionally, we showed that DDR1 inhibition affected the non-canonical WNT signaling pathway in human skeletal cells and decreased proteoglycan production in chondrocytes. These findings suggest that DDR1 is a new gene involved in the group of chondrodysplasias with multiple dislocations and highlights its essential role in human skeletal and brain development.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875807","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 role of sympathetic control in bone vasculature: insights from spinal cord injury.","authors":"Maria Sukhoplyasova, Jason W Hamner, Adina E Draghici","doi":"10.1093/jbmr/zjae204","DOIUrl":"https://doi.org/10.1093/jbmr/zjae204","url":null,"abstract":"<p><p>Bone vasculature is richly innervated by an extensive network of sympathetic nerves. However, our understanding of bone blood flow regulation and its contribution to human bone health is limited. Here, we further our previous findings by characterizing bone vascular responses in the absence of sympathetic control - studying individuals with spinal cord injury (SCI), a population with known peripheral sympathetic disruption. We assessed tibial vascular responses to isometric handgrip exercise (IHE) in individuals with SCI (n = 12) and controls (n = 12). When sustained to fatigue, IHE increases perfusion pressure and sympathetic vasoconstriction in the non-active tissues of the legs. During IHE, we measured blood pressure, whole leg blood velocity via ultrasound, and tibial perfusion (as hemoglobin content) via near-infrared spectroscopy. Controls demonstrated active sympathetic vasoconstriction in the whole leg (i.e., increased vascular resistance, arterial pressure/leg blood velocity) and tibia (i.e., decreased hemoglobin). In contrast, SCI individuals demonstrated modest whole leg vasoconstriction with lesser increases in vascular resistance than controls (P<.04). Tibial vasculature evidenced absent or blunted vasoconstriction compared to controls (P<.01), indicated by increasing tibial hemoglobin until plateauing at higher pressure levels. This suggests that, in the absence of sympathetic control, tibial vascular response may involve other regulatory mechanisms like myogenic vasoconstriction. Lastly, we leveraged existent whole-body Dual Energy X-ray Absorptiometry scans in a subgroup of nine individuals with SCI and we found a strong relationship between leg bone mineral density (BMD) and tibial hemoglobin at end of IHE (r2 = 0.67, P<.01). Our findings indicate that in the absence of sympathetic mechanisms, myogenic control may play a compensatory role in regulating blood flow, though to a lesser extent in bone compared to muscle. The close relationship between lesser declines in bone blood content and higher BMD underscores the link between blood flow and bone health.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875724","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":"Letter to the editor in response to Duan X, et al, CYP4A22 loss-of-function causes a new type of vitamin D-dependent rickets (VDDR1C).","authors":"Michael A Levine, Dong Li, Jeffrey Roizen, David Weber","doi":"10.1093/jbmr/zjae203","DOIUrl":"https://doi.org/10.1093/jbmr/zjae203","url":null,"abstract":"<p><p>Duan X, et al, report that CYP4A22 loss-of-function causes a new form of vitamin D-dependent rickets. Here we describe the basis for our rejection of their proposal and provide evidence that the CYP4A22 variant that they have identified (c.901del, p.Glu301Argfs*80 (NM_001010969.4)), is a common allelic variant that is particularly prevalent in the East Asian population that includes the patients that they studied. Finally, we submit that the two patients are more likely to have X-linked Hypophosphatemic rickets than vitamin D dependent rickets.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875801","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":"Modification of bone architecture following sleeve gastrectomy: a 5-year follow-up.","authors":"Laurent Maïmoun, Safa Aouinti, Marion Puech, Patrick Lefebvre, Ludovic Humbert, Mélanie Deloze, Pascal de Santa Barbara, Lisa Maïmoun-Nande, Vincent Boudousq, Jean-Paul Cristol, Eric Renard, Marie-Christine Picot, Denis Mariano-Goulart, David Nocca","doi":"10.1093/jbmr/zjae202","DOIUrl":"https://doi.org/10.1093/jbmr/zjae202","url":null,"abstract":"<p><p>Bariatric surgery induces a decrease in areal bone mineral density (aBMD), but the long-term effect on trabecular and cortical volumetric bone mineral density (vBMD) has not been well assessed. The main aim of this 5-year longitudinal study was to investigate the changes following sleeve gastrectomy (SG) in aBMD, bone turnover markers and trabecular and cortical vBMD. Forty-five patients with obesity were assessed before and 1, 2 and 5 years after SG. Trabecular and cortical vBMD, cortical thickness and structural parameters were assessed by 3D-Shaper® software at hip. Values of bone turnover markers peaked after 1 year and decreased after 2 and 5 years, but without returning to baseline values. aBMD decreased mostly at femoral neck(-9.7%) and total hip(-10.7%) over the 5 years, with the greatest loss occurring at 1 year(-5.9% and -6.3%, respectively). A similar profile of decrease was observed for integral hip vBMD with significant decreases of 6.6%, 7.7% and 10.7% after 1, 2 and 5 years, mainly due to a reduction in the trabecular (10.5%, 12.0% and 17.2%, respectively) rather than cortical (1.4%, 1.9% and 2.9%, respectively) component. A modest decrease in mean cortical thickness (2.5%, 2.8% and 3.9%, respectively) and an alteration in the structural parameters were concomitantly observed. Older age and greater body weight loss were the factors most associated with an increased loss of aBMD and vBMD. In conclusion, the study demonstrates that SG induces not only an alteration in bone turnover and aBMD, but also a reduction in vBMD at hip, predominantly due to trabecular component deterioration as determined by 3D-Shaper® software. The maintenance of bone deterioration for at least 5 years - that is, after 4 years of relative body weight stabilization or minimal weight regain - suggests the need for a therapeutic approach to preserve bone health in patients who undergo SG.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851805","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 relationship between baseline BMD and fracture incidence in the placebo groups of RCTs using individual patient data from the FNIH-ASBMR-SABRE Project.","authors":"Marian Schini, Li-Yung Lui, Tatiane Vilaca, Susan K Ewing, Austin Thompson, Douglas C Bauer, Mary L Bouxsein, Dennis M Black, Richard Eastell","doi":"10.1093/jbmr/zjae201","DOIUrl":"https://doi.org/10.1093/jbmr/zjae201","url":null,"abstract":"<p><p>We have proposed to the Food and Drug Administration (FDA) that treatment-related increases in total hip bone mineral density (TH BMD) at two years could be a surrogate endpoint for fracture risk reduction in clinical trials. The qualification of a surrogate includes a strong association of the surrogate with the clinical outcome. We compiled a large database of individual patient data (IPD) through the FNIH-ASBMR-SABRE project, and this analysis aimed to assess the relationship between baseline BMD and fracture risk in the placebo groups. We estimated the association of baseline TH, femoral neck (FN) and lumbar spine (LS) BMD with fracture risk using IPD from the combined placebo groups which included data from 46 666 placebo participants in 25 randomised controlled trials (RCTs). We estimated the relative risk (RR) of fracture per standard deviation (SD) decrease in baseline BMD using logistic regression models for radiographic vertebral fractures and proportional hazards models for hip, non-vertebral, \"all\" and \"all clinical\" fractures. Total person-years in the combined placebo groups was 250 662 (mean baseline age 70.2 ± 7.2 years, mean TH BMD T-score -1.97 ± 0.90). We observed significant relationships between baseline TH BMD and vertebral (RR = 1.55/SD), hip (RR = 2.27), non-vertebral (RR = 1.31), all (RR = 1.43) and all clinical (RR = 1.35) fracture risk. Fracture risk estimates were similar for FN BMD and after adjustment for age, race and study. Fracture incidence increased with decreasing TH BMD quintile, confirming the strong graded association between TH BMD and fracture risk. There was a strong relationship between LS BMD and vertebral fracture risk (RR = 1.56/SD), but only a weak association with non-vertebral (RR = 1.07) and no association with hip (RR = 1.01) fracture risk. These data support the very strong relationship between hip BMD and fracture risk and provide supporting rationale for change in TH BMD as a surrogate for fracture risk reduction in future RCTs.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833173","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":"Pharmacogenetic and microRNA mechanisms of beta blocker use on bone.","authors":"Christine W Lary, Elizabeth J Atkinson, Jennifer Spillane, Zannatun Nayema, Tyler A Roy, Rebecca Peters, Griffin T Scott, Hongyu Chen, Archana Nagarajan, Aaron Brown, Katherine J Motyl, David G Monroe, Sundeep Khosla","doi":"10.1093/jbmr/zjae200","DOIUrl":"https://doi.org/10.1093/jbmr/zjae200","url":null,"abstract":"<p><p>Motivated by studies showing an association between beta blocker (BB) use and positive bone outcomes, a pilot randomized control trial (RCT) was performed at the Mayo Clinic which randomized postmenopausal women to placebo, propranolol (40 or 80 mg twice daily), atenolol (50 mg/day), or nebivolol (5 mg/day) to determine changes in bone turnover markers (BTMs) and in bone mineral density (BMD) over 20 weeks. Pharmacogenetic effects and microRNA-mediated mechanisms involving beta adrenergic receptor and related genes have previously been found. We sought to validate these effects and discover new candidates in an ancillary study to the pilot clinical trial. We genotyped all participants and performed microRNA (miRNA) sequencing at baseline and at 20 weeks for 24 participants from the atenolol or placebo groups. We discovered several variants in ADRB1, ADRB2, and HDAC4 which showed significant pharmacogenetic effects with BMD at multiple sites and with BTMs. Our miRNA results showed a significant treatment effect for miR-19a-3p over time with atenolol use in the low-responder group compared to placebo. Overall, the longitudinal miRNA analysis showed a large number of miRNAs which were up-regulated over the trial in the low responders but not the high responders compared to placebo, of which miR-19a-3p was one example. Finally, we compared the response to atenolol treatment for cardiovascular traits (pulse, blood pressure) with the response for the bone resorption marker, CTX, and found a largely independent effect. Our results have implications for personalized therapy and for understanding mechanisms of BB treatment effect on bone.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823477","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":"Cardiovascular disease in adults with osteogenesis imperfecta: Clinical characteristics, care recommendations and research priorities identified using a modified Delphi technique.","authors":"Lars Folkestad, Siddharth K Prakash, Sandesh C S Nagamani, Niels Holmark Andersen, Erin Carter, Jannie Dahl Hald, Riley J Johnson, Bente Langdahl, Eleanor M Perfetto, Cathleen Raggio, Stuart Ralston, Robert A Sandhaus, Oliver Semler, Laura Tosi, Eric Orwoll","doi":"10.1093/jbmr/zjae197","DOIUrl":"https://doi.org/10.1093/jbmr/zjae197","url":null,"abstract":"<p><p>Osteogenesis imperfecta (OI) is a multisystem disorder most often caused by pathogenic variants in genes that encode type I collagen. Type I collagen is abundant not only in bone but also in multiple tissues including skin, tendons, cornea, blood vessels and heart. Thus, OI can be expected to affect cardiovascular system, and there are numerous reports of cardiovascular disease (CVD) in people with OI. However, there is no consensus on how CVD in OI should be assessed or managed. To fill this gap, a multidisciplinary group was convened to develop clinical guidance. The work included a systematic review of the available literature and, using a modified Delphi approach, the development of a series of statements summarizing current knowledge. Fourteen clinical recommendations were developed to guide clinicians, patients, and stakeholders about an approach for CVD in adults with OI. This paper describes how the work was conducted and provides the background and rationale for each recommendation. Furthermore, we highlight knowledge gaps and suggest research priorities for the future study of CVD in OI.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811693","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":"An activating CaSR variant with biased signaling reveals a critical residue for Gα11 coupling.","authors":"Matthew R Benson, Rachael A Wyatt, Michael A Levine, Caroline M Gorvin","doi":"10.1093/jbmr/zjae199","DOIUrl":"https://doi.org/10.1093/jbmr/zjae199","url":null,"abstract":"<p><p>Autosomal dominant hypocalcemia (ADH) is due to enhanced calcium-dependent signaling caused by heterozygous gain-of-function (GOF) variants in the CASR gene (ADH1) or in the GNA11 gene, encoding Gα11 (ADH2). Both ADH1 and ADH2 are associated with hypocalcemia and normal or inappropriately low levels of circulating PTH. ADH1 patients typically manifest hypercalciuria, while ADH2 is associated with short stature in approximately 42% of cases. We evaluated a 10-year-old boy with hypoparathyroidism and short stature. Biochemical analyses revealed hypocalcemia, hyperphosphatemia and inconsistent hypercalciuria. Genetic analyses revealed a de novo heterozygous p.Leu723Arg variant in CASR. We characterized the expression of recombinant wild type and Leu723Arg CaSR proteins in HEK293 cells and assessed G protein activation in vitro by CaSR using Bioluminescence Resonance Energy Transfer (BRET). Transient expression studies showed the Leu723Arg variant was normally expressed but resulted in a significantly lower EC50 for extracellular calcium activation of G11 but not other G proteins (i.e. Gi, Gq, Gs). The Leu723Arg substitution has a novel GOF phenotype that leads to biased CaSR activation of G11 signaling, suggesting that residue 723 specifies activation of G11 but not other G proteins. Similar studies of a previously described CaSR variant associated with hypoparathyroidism and short stature, Leu616Val, showed no changes in any G protein pathways, indicating it is likely to be a benign variant. Given the preferential activation of G11 by the Leu723Arg CaSR variant, we propose that the patient's short stature shares a similar basis to that in patients with ADH2 due to GOF variants in GNA11.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805747","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":"Bone microarchitecture and strength in men and women with PLS3 gene variants assessed with HR-pQCT.","authors":"Zografia Zervou, Melissa S A M Bevers, Caroline E Wyers, Hennie T Bruggenwirth, Serwet Demirdas, Joop P van den Bergh, M Carola Zillikens","doi":"10.1093/jbmr/zjae186","DOIUrl":"https://doi.org/10.1093/jbmr/zjae186","url":null,"abstract":"<p><p>X-linked osteoporosis, caused by PLS3 genetic variants, is a rare bone disease, clinically affecting mainly men. Limited data are available on bone microarchitecture and genotype-phenotype correlations in this disease. Our aims were to assess bone microarchitecture and strength in adults with PLS3 variants using high-resolution peripheral quantitative computed tomography (HR-pQCT) and to explore differences in the phenotype from HR-pQCT between PLS3 variants. HR-pQCT scans were obtained from the distal radius and tibia of 13 men and three women with PLS3 variants. Results were compared with age- and sex-matched controls from a normative dataset from literature and expressed as Z-scores. Median age was 46 years for men and 48 years for women. In men, total bone area was large (median Z-score: 1.33 radius; 1.46 tibia) due to a large trabecular area (+1.73 radius; +1.87 tibia), while the cortical area was small (-2.61 radius; -2.84 tibia). Total volumetric bone mineral density (BMD) was low due to low trabecular (-3.46 radius; -3.37 tibia) and cortical BMD (-2.87 radius; -2.26 tibia). Regarding bone microarchitecture, the largest deviations were found in trabecular number (-2.18 radius; -1.64 tibia), trabecular separation (+2.32 radius; +1.65 tibia), and cortical thickness (-2.99 radius; -2.46 tibia), whereas trabecular thickness and cortical porosity were normal (-0.36 and -0.58 radius; 0.09 and -0.79 tibia). Additionally, failure load was low (-2.39 radius; -2.2 tibia). Results in the women deviated less from normative data. Men with frameshift/nonsense variants seemed to have more deviant trabecular and cortical microarchitecture and strength, at both scan locations, than those with missense/in-frame insertion variants. In conclusion, HR-pQCT provides valuable insights into bone area, BMD, microarchitecture, and strength in adults with PLS3 variants and can be used to explore genotype-phenotype relationships. Longitudinal analyses in larger groups are needed to study the natural course of the disease and treatment effects.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805750","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":"Commentary: Romosozumab following denosumab improves lumbar spine bone mineral density and trabecular bone score greater than denosumab continuation in postmenopausal women.","authors":"S Ferrari","doi":"10.1093/jbmr/zjae192","DOIUrl":"https://doi.org/10.1093/jbmr/zjae192","url":null,"abstract":"","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805752","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}