Journal of Bone and Mineral Research最新文献

{"title":"Biochemical Markers of Calcium and Bone Metabolism during and after Lactation in Ugandan Women with HIV on Universal Maternal Antiretroviral Therapy","authors":"Florence Nabwire,&nbsp;Matthew M. Hamill,&nbsp;Mary Glenn Fowler,&nbsp;Josaphat Byamugisha,&nbsp;Adeodata Kekitiinwa,&nbsp;Ann Prentice","doi":"10.1002/jbmr.4866","DOIUrl":"https://doi.org/10.1002/jbmr.4866","url":null,"abstract":"<p>We reported accentuated lactational decreases in areal bone mineral density and only partial skeletal recovery after lactation in Ugandan women with HIV (WWH) initiated on tenofovir disoproxil fumarate-based antiretroviral therapy (TDF-based ART) during pregnancy compared to women without HIV (REF). WWH also had higher breast milk calcium in the first months of lactation. To investigate the mechanisms, we measured bone turnover markers (bone resorption: C-terminal telopeptide [CTX]; bone formation: procollagen type 1 N-terminal propeptide [P1NP], bone-specific and total alkaline phosphatase [BALP, TALP]), hormones (parathyroid hormone [PTH], intact fibroblast growth factor 23 [FGF23], 1,25-dihydroxyvitamin D [1,25(OH)₂D]), vitamin D status (25-hydroxyvitamin D [25OHD]), and indices of mineral metabolism and renal function. Blood and urine samples collected at 36 weeks of gestation, 14 and 26 weeks of lactation, and 3–6 months after lactation were analyzed. Mean 25OHD was &gt;50 nmol/L throughout. Both groups experienced similar biochemical changes during pregnancy and lactation to women in other settings, but within these patterns, the two groups differed significantly. Notably, WWH had higher PTH (+31%) and lower 1,25(OH)₂D (−9%) and TmP/GFR (−9%) throughout, lower P1NP (−27%) and plasma phosphate (−10%) in pregnancy, higher CTX (+15%) and BALP (+19%), and lower eGFR (−4%) during and after lactation. P1NP/CTX ratio was lower in WWH than REF in pregnancy (−21%), less so in lactation (−15%), and similar after lactation. Additionally, WWH had lower plasma calcium (−5%), lower FGF23 (−16%) and fasting urinary calcium (−34%) at one or both lactation timepoints, and higher fasting urinary phosphate (+22%) at 26 weeks of lactation and after lactation. These differences resemble reported TDF effects, especially raised PTH, increased bone resorption, decreased bone formation, and decreased renal function, and may explain the observed differences in bone mineral density and breast milk calcium. Further studies are needed to determine whether HIV and TDF-based ART have long-term consequences for maternal bone health and offspring growth. © 2023 The Authors. <i>Journal of Bone and Mineral Research</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 9","pages":"1296-1311"},"PeriodicalIF":6.2,"publicationDate":"2023-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4866","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41081691","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":"RNA Sequencing of Urine-Derived Cells for the Characterization and Diagnosis of Osteogenesis Imperfecta","authors":"Karissa Ludwig,&nbsp;Zenghui Wu,&nbsp;Ghalib Bardai,&nbsp;Patrizia Mason,&nbsp;Leanne M Ward,&nbsp;Pierre Moffatt,&nbsp;Frank Rauch","doi":"10.1002/jbmr.4865","DOIUrl":"https://doi.org/10.1002/jbmr.4865","url":null,"abstract":"<p>DNA sequencing is a reliable tool for identifying genetic variants in osteogenesis imperfecta (OI) but cannot always establish pathogenicity, particularly in variants altering splicing. RNA sequencing can provide functional evidence of the effect of a variant on the transcript but requires cells expressing the relevant genes. Here, we used urine-derived cells (UDC) to characterize genetic variants in patients with suspected or confirmed OI and provide evidence on the pathogenicity of variants of uncertain significance (VUS). Urine samples were obtained from 45 children and adolescents; UDC culture was successful in 40 of these participants (age range 4–20 years, 21 females), including 18 participants with OI or suspected OI who had a candidate variant or VUS on DNA sequencing. RNA was extracted from UDC and sequenced on an Illumina NextSeq550 device. Principal component analysis showed that the gene expression profiles of UDC and fibroblasts (based on Genotype Tissue Expression [GTEx] Consortium data) clustered close together and had less variability than those of whole blood cells. Transcript abundance was sufficient for analysis by RNA sequencing (defined as a median gene expression level of ≥10 transcripts per million) for 25 of the 32 bone fragility genes (78%) that were included in our diagnostic DNA sequencing panel. These results were similar to GTEx data for fibroblasts. Abnormal splicing was identified in 7 of the 8 participants with pathogenic or likely pathogenic variants in the splice region or deeper within the intron. Abnormal splicing was also observed in 2 VUS (<i>COL1A1</i> c.2829+5G&gt;A and <i>COL1A2</i> c.693+6T&gt;G), but no splice abnormality was observed in 3 other VUS. Abnormal deletions and duplications could also be observed in UDC transcripts. In conclusion, UDC are suitable for RNA transcript analysis in patients with suspected OI and can provide functional evidence for pathogenicity, in particular of variants affecting splicing. © 2023 The Authors. <i>Journal of Bone and Mineral Research</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 8","pages":"1125-1134"},"PeriodicalIF":6.2,"publicationDate":"2023-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4865","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6170212","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":"Doubling Down on Wnt Signaling to Overcome Myeloma Bone Disease","authors":"Jesús Delgado-Calle,&nbsp;G. David Roodman","doi":"10.1002/jbmr.4863","DOIUrl":"https://doi.org/10.1002/jbmr.4863","url":null,"abstract":"Multiple myeloma is a hematologic malignancy characterized by devastating lytic bone disease. The growth of myeloma cells in bone stimulates osteoclastic resorption, resulting in the development of osteolytic lesions that weaken the bone. These lytic lesions rarely heal, even in patients in complete remission, due to a concomitant suppression of bone formation. With improved medical treatment for multiple myeloma, patients are living longer, and proper management of the bone disease has become paramount to reducing fractures and bone pain and improving the quality of life and survival of myeloma patients. Bisphosphonates and denosumab are used in the clinic to treat myeloma bone disease but have only minor effects, if any, on repairing damaged bone. Thus, bone disease remains a major challenge in managing multiple myeloma, and new therapeutic approaches are desperately needed. Multiple signaling pathways and factors produced or induced by myeloma cells in the bone microenvironment have been shown to contribute to the abnormal bone remodeling characteristic ofmyeloma bonedisease. In the last decade, theWnt signaling pathway and its components have emerged as key regulators of bone homeostasis and repair. The binding of canonical Wnt ligands to the Wnt coreceptors low-density lipoprotein receptorrelated protein (LRP) 5 or 6 initiates a cascade of events that prevent the phosphorylation of β-catenin and its proteasomal degradation, leading to its translocation into the nucleus, where it associates with other transcription factors to control gene transcription. The Wnt signaling pathway is also modulated by extracellular antagonists such as Dickkopf-related protein 1 (DKK1), sclerostin, or sclerostin domain containing 1 (SOSTDC1), which block the binding of Wnt ligands to LRP5/6. Neutralizing antibodies to secreted antagonists of Wnt signaling, such as DKK1 and sclerostin, stimulate bone formation and can suppress bone resorption. In multiple myeloma patients, the levels of sclerostin and DKK1 are elevated. Priorwork tested anti-DKK1or anti-sclerostin antibodies in mouse models of myeloma-induced bone disease and observed promising effects on bonemass, primarily due to increases in osteoblast number and restoration of bone formation. In this issue, Simic and colleagues examine the bone effects of a novel anti-LRP6 antibody (anti-LRP6) that potentiates Wnt1-class ligand signaling. They report that anti-LRP6 increases bonemass in mice not bearing tumors and prevents the cancellous bone destruction induced by multiple myeloma cells. When combined with a neutralizing antibody against DKK1 (anti-DKK1), anti-LRP6 leads to even higher cancellous bone mass and improves bone strength in both naïve and tumor-bearing mice. These findings are consistent with the superior increases in bone mass and improved fracture repair seen with the simultaneous targeting of DKK1 and sclerostin using a bispecific neutralizing antibody in naïve mice. Interestingly, also in thi","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 6","pages":"812-813"},"PeriodicalIF":6.2,"publicationDate":"2023-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://asbmr.onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4863","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6101766","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":"Pro-Inflammatory Proteins Associated with Frailty and Its Progression—A Longitudinal Study in Community-Dwelling Women","authors":"Adam Mitchell,&nbsp;Linnea Malmgren,&nbsp;Patrik Bartosch,&nbsp;Fiona Elizabeth McGuigan,&nbsp;Kristina E. Akesson","doi":"10.1002/jbmr.4861","DOIUrl":"https://doi.org/10.1002/jbmr.4861","url":null,"abstract":"<p>The complex pathophysiology underlying biological aging creates challenges for identifying biomarkers associated with frailty. This longitudinal, nontargeted proteomics study aimed to identify proteins associated with frailty, particularly the change from nonfrail to frail. The population-based Osteoporosis Prospective Risk Assessment cohort includes women all of whom are 75 years old at inclusion (<i>n</i> = 1044) and reassessed at 80 years (<i>n</i> = 715) and 85 years (<i>n</i> = 382). A deficits in health frailty index (FI) and 92 plasma proteins (Olink CVD-II panel) were available at all ages. The identical age facilitated differentiating chronological and biological aging. Bidirectional analyses, performed cross-sectionally and longitudinally, used regression models controlled for false discovery rate (FDR), across 5- and 10-year time windows and longitudinal mixed models. Frailty outcomes were frailty index, frailty status (frail defined as FI ≥ 0.25), change in frailty index, and change in frailty status, together with protein expression or change in protein expression. Elevated levels of 32 proteins were positively associated with the FI, cross-sectionally at all ages (range: β-coefficients 0.22–2.06; FDR 0.021–0.024), of which 18 were also associated with frailty status (range: odds ratios 1.40–5.77; FDR 0.022–0.016). Based on the accrued data, eight core proteins (CD4, FGF23, Gal-9, PAR-1, REN, TNFRSF10A TNFRSF11A, and TNFRSF10B) are proposed. A one-unit change in the FI was additively associated with increased protein expression over 5 and 10 years (range: β-coefficients 0.52–1.59; <i>p</i> &lt; 0.001). Increments in baseline FI consistently associated with a change in protein expression over time (5 years, β-range 0.05–1.35; 10 years, β-range 0.51–1.48; all <i>p</i> &lt; 0.001). A one-unit increase in protein expression was also associated with an increased probability of being frail (FI ≥ 0.25) (β-range: 0.14–0.61). Mirroring the multisystem deterioration that typifies frailty, the proteins and their associated biological pathways reflect pathologies, including the renal system, skeletal homeostasis, and TRAIL-activated apoptotic signaling. The core proteins are compelling candidates for understanding the development and progression of frailty with advancing age, including the intrinsic musculoskeletal component. © 2023 The Authors. <i>Journal of Bone and Mineral Research</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 8","pages":"1076-1091"},"PeriodicalIF":6.2,"publicationDate":"2023-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4861","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5880862","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":"Nonalcoholic Fatty Liver Disease Is Associated With Decreased Bone Mineral Density in Adults: A Systematic Review and Meta-Analysis","authors":"Ying-Hao Su,&nbsp;Kuo-Liong Chien,&nbsp;Shu-Hua Yang,&nbsp;Wei-Tso Chia,&nbsp;Jen-Hau Chen,&nbsp;Yen-Ching Chen","doi":"10.1002/jbmr.4862","DOIUrl":"https://doi.org/10.1002/jbmr.4862","url":null,"abstract":"This systematic review and meta‐analysis aimed to investigate the effect of nonalcoholic fatty liver disease (NAFLD) on bone mineral density (BMD) and the risk of osteoporosis and osteoporotic fracture in adults. We searched PubMed, MEDLINE, Embase, CINAHL, Web of Science, Cochrane Library, and Scopus for observational studies published from inception to January 2023 that reported adjusted effect sizes of NAFLD on BMD, osteopenia/osteoporosis, and osteoporotic fracture. The data were synthesized using multilevel and random‐effects models. A total of 19 studies were included; of these, nine (21,294 participants) evaluated the effect of NAFLD on BMD, six (133,319 participants) investigated the risk of osteoporosis, and five (227,901 participants) assessed the risk of osteoporotic fracture. This meta‐analysis showed that NAFLD was associated with decreased BMD (mean difference −0.019 g/cm2, 95% confidence interval [CI] −0.036 to −0.002, I2 = 93%) and increased risks of osteoporosis (adjusted risk ratio [RR] = 1.28, 95% CI 1.08 to 1.52, I2 = 84%) and osteoporotic fractures (adjusted RR = 1.17, 95% CI 1.00 to 1.37, I2 = 67%). Subgroup analyses revealed that NAFLD had a significantly detrimental effect on BMD in men and on the BMD of the femoral neck and total hip. Stratified analyses by ethnicity demonstrated that NAFLD was not associated with BMD, osteoporosis, or osteoporotic fracture in non‐Asian populations. The publication bias of all included studies was low; however, there was considerable heterogeneity among the studies, warranting a careful interpretation of the findings. Overall, our results suggest that NAFLD is associated with decreased BMD and an increased risk of osteoporosis or osteoporotic fractures. Male sex and the BMD of the femoral neck and total hip may be potential risk factors for decreased BMD in adults with NAFLD. Additionally, ethnic disparities were observed between Asian and non‐Asian populations regarding BMD and osteoporotic fractures. © 2023 American Society for Bone and Mineral Research (ASBMR).","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 8","pages":"1092-1103"},"PeriodicalIF":6.2,"publicationDate":"2023-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5788055","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":"Correction to ‘Insulin-Like Growth Factor 2 (IGF-2) Potentiates BMP-9-Induced Osteogenic Differentiation and Bone Formation’","authors":"","doi":"10.1002/jbmr.4830","DOIUrl":"https://doi.org/10.1002/jbmr.4830","url":null,"abstract":"<p>\u0000 <span>Chen, L</span> <span>Jiang, W</span>, <span>Huang, J</span>, <span>He, B-C</span>, <span>Zuo, G-W</span>, <span>Zhang, W</span>, <span>Luo, Q</span>, <span>Shi, Q</span>, <span>Zhang, B-Q</span>, <span>Wagner, ER</span>, <span>Luo, J</span>, <span>Tang, M</span>, <span>Wietholt, C</span>, <span>Luo, X</span>, <span>Bi, Y</span>, <span>Su, Y</span>, <span>Liu, B</span>, <span>Kim, SH</span>, <span>He, CJ</span>, <span>Hu, Y</span>, <span>Shen, J</span>, <span>Rastegar, F</span>, <span>Huang, E</span>, <span>Gao, Y</span>, <span>Gao, J-L</span>, <span>Zhou, J-Z</span>, <span>Reid, RR</span>, <span>Luu, HH</span>, <span>Haydon, RC</span>, <span>He, T-C</span>, <span>Deng, Z-L</span> (<span>2010</span>) <span>Insulin-like growth factor 2 (IGF-2) potentiates BMP-9-induced osteogenic differentiation and bone formation</span>. <i>J Bone Miner Res.</i> 2010; <span>25</span>(<span>11</span>): <span>2447</span>–<span>2459</span>. doi: https://doi.org/10.1002/jbmr.133\u0000 </p><p>In the published article, the authors found an image assembly error in <b>Figure 1C</b>, in which the image for “C3H10T1/2 (Ad-IGFP)” group was erroneously duplicated with the image from the “BMP9 + RFP” group of <b>Figure 3A</b>. The corrected figure is shown below. As shown in the corrected <b>Figure 1C</b>, this error does not adversely impact the conclusion of the original work. The authors apologize for any inconvenience caused by the error to the journal and scientific community.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 6","pages":"929"},"PeriodicalIF":6.2,"publicationDate":"2023-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4830","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5867240","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":"Testosterone Restores Body Composition, Bone Mass, and Bone Strength Following Early Puberty Suppression in a Mouse Model Mimicking the Clinical Strategy in Trans Boys","authors":"Vanessa Dubois,&nbsp;Silvia Ciancia,&nbsp;Stefanie Doms,&nbsp;Sarah El Kharraz,&nbsp;Vera Sommers,&nbsp;Na Ri Kim,&nbsp;Karel David,&nbsp;Jolien Van Dijck,&nbsp;Roger Valle-Tenney,&nbsp;Christa Maes,&nbsp;Leen Antonio,&nbsp;Brigitte Decallonne,&nbsp;Geert Carmeliet,&nbsp;Frank Claessens,&nbsp;Martine Cools,&nbsp;Dirk Vanderschueren","doi":"10.1002/jbmr.4832","DOIUrl":"10.1002/jbmr.4832","url":null,"abstract":"<div>\u0000 \u0000 <p>Transgender youth increasingly present at pediatric gender services. Some of them receive long-term puberty suppression with gonadotropin-releasing hormone analogues (GnRHa) before starting gender-affirming hormones (GAH). The impact of GnRHa use started in early puberty on bone composition and bone mass accrual is unexplored. It is furthermore unclear whether subsequent GAH fully restore GnRHa effects and whether the timing of GAH introduction matters. To answer these questions, we developed a mouse model mimicking the clinical strategy applied in trans boys. Prepubertal 4-week-old female mice were treated with GnRHa alone or with GnRHa supplemented with testosterone (T) from 6 weeks (early puberty) or 8 weeks (late puberty) onward. Outcomes were analyzed at 16 weeks and compared with untreated mice of both sexes. GnRHa markedly increased total body fat mass, decreased lean body mass, and had a modest negative impact on grip strength. Both early and late T administration shaped body composition to adult male levels, whereas grip strength was restored to female values. GnRHa-treated animals showed lower trabecular bone volume and reduced cortical bone mass and strength. These changes were reversed by T to female levels (cortical bone mass and strength) irrespective of the time of administration or even fully up to adult male control values (trabecular parameters) in case of earlier T start. The lower bone mass in GnRHa-treated mice was associated with increased bone marrow adiposity, also reversed by T. In conclusion, prolonged GnRHa use started in prepubertal female mice modifies body composition toward more fat and less lean mass and impairs bone mass acquisition and strength. Subsequent T administration counteracts GnRHa impact on these parameters, shaping body composition and trabecular parameters to male values while restoring cortical bone architecture and strength up to female but not male control levels. These findings could help guide clinical strategies in transgender care. © 2023 American Society for Bone and Mineral Research (ASBMR).</p>\u0000 </div>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 10","pages":"1497-1508"},"PeriodicalIF":6.2,"publicationDate":"2023-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9946149","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":"Germ-Free C57BL/6 Mice Have Increased Bone Mass and Altered Matrix Properties but Not Decreased Bone Fracture Resistance","authors":"Ghazal Vahidi,&nbsp;Maya Moody,&nbsp;Hope D. Welhaven,&nbsp;Leah Davidson,&nbsp;Taraneh Rezaee,&nbsp;Ramina Behzad,&nbsp;Lamya Karim,&nbsp;Barbara A. Roggenbeck,&nbsp;Seth T. Walk,&nbsp;Stephen A. Martin,&nbsp;Ronald K. June,&nbsp;Chelsea M. Heveran","doi":"10.1002/jbmr.4835","DOIUrl":"https://doi.org/10.1002/jbmr.4835","url":null,"abstract":"<p>The gut microbiome impacts bone mass, which implies a disruption to bone homeostasis. However, it is not yet clear how the gut microbiome affects the regulation of bone mass and bone quality. We hypothesized that germ-free (GF) mice have increased bone mass and decreased bone toughness compared with conventionally housed mice. We tested this hypothesis using adult (20- to 21-week-old) C57BL/6J GF and conventionally raised female and male mice (<i>n</i> = 6–10/group). Trabecular microarchitecture and cortical geometry were measured from micro–CT of the femur distal metaphysis and cortical midshaft. Whole-femur strength and estimated material properties were measured using three-point bending and notched fracture toughness. Bone matrix properties were measured for the cortical femur by quantitative back-scattered electron imaging and nanoindentation, and, for the humerus, by Raman spectroscopy and fluorescent advanced glycation end product (fAGE) assay. Shifts in cortical tissue metabolism were measured from the contralateral humerus. GF mice had reduced bone resorption, increased trabecular bone microarchitecture, increased tissue strength and decreased whole-bone strength that was not explained by differences in bone size, increased tissue mineralization and fAGEs, and altered collagen structure that did not decrease fracture toughness. We observed several sex differences in GF mice, most notably for bone tissue metabolism. Male GF mice had a greater signature of amino acid metabolism, and female GF mice had a greater signature of lipid metabolism, exceeding the metabolic sex differences of the conventional mice. Together, these data demonstrate that the GF state in C57BL/6J mice alters bone mass and matrix properties but does not decrease bone fracture resistance. © 2023 The Authors. <i>Journal of Bone and Mineral Research</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 8","pages":"1154-1174"},"PeriodicalIF":6.2,"publicationDate":"2023-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4835","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5825179","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":"Association of Preterm Birth and Low Birthweight with Bone Fractures during Childhood","authors":"Ilari Kuitunen,&nbsp;Reijo Sund,&nbsp;Ulla Sankilampi","doi":"10.1002/jbmr.4833","DOIUrl":"https://doi.org/10.1002/jbmr.4833","url":null,"abstract":"<p>Preterm birth and low birthweight have been associated with increased fracture risk in children. Our aim was to analyze bone fractures during childhood in preterm, and low-birthweight newborns compared to full-term and normal-birthweight newborns. We conducted a nationwide register-based cohort study in Finland from 1998 to 2017 and utilized the Medical Birth Register and Care Register for Health Care. All newborns alive 28 days after birth were included, and data on all fracture visits in specialized healthcare units were gathered. Incidences per 100,000 person-years with 95% confidence intervals (CI) were calculated, and comparisons were made by incidence rate ratios (IRRs). Kaplan–Meier analysis was used to analyze the timing of fractures during childhood (0–20 years). We included a total of 997,468 newborns and 95,869 fractures; the mean follow-up was 10.0 years, and the overall incidence of fractures was 963 per 100,000 person-years. Very preterm (&lt;32 gestational weeks) newborns had 23% lower fracture incidence than term newborns (IRR 0.77; CI: 0.70–0.85). Preterm newborns (32 to 36 gestational weeks) had a fracture rate (IRR 0.98; CI: 0.95–1.01) similar to that of term newborns. Birthweight showed a linear increase in the fracture rates as newborns with birthweight less than 1000 g had the lowest fracture incidence of 773 per 100,000 person-years and the highest incidence (966 per 100,000 person-years) was among newborns with birthweight 2500 g or more. Children born very preterm or with extremely low birthweight have in general a lower fracture incidence during childhood compared to children born full term and with normal birthweight. These findings possibly reflect, in addition to improvements of neonatal intensive care and early nutrition, the fact that childhood fracture incidences are more dependent on issues other than early life events. © 2023 The Authors. <i>Journal of Bone and Mineral Research</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 8","pages":"1116-1124"},"PeriodicalIF":6.2,"publicationDate":"2023-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4833","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5768392","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":"miR-196b-5p Regulates Osteoblast and Osteoclast Differentiation and Bone Homeostasis by Targeting SEMA3A","authors":"Yan Xie,&nbsp;Jie Zhou,&nbsp;Lijie Tian,&nbsp;Yuan Dong,&nbsp;Hairui Yuan,&nbsp;Endong Zhu,&nbsp;Xiaoxia Li,&nbsp;Baoli Wang","doi":"10.1002/jbmr.4834","DOIUrl":"https://doi.org/10.1002/jbmr.4834","url":null,"abstract":"<div>\u0000 \u0000 <p>miR-196b-5p plays a role in various malignancies. We have recently reported its function in regulating adipogenesis. However, it remains to be clarified whether and how miR-196b-5p affects bone cells and bone homeostasis. In this study, in vitro functional experiments showed an inhibitory effect of miR-196b-5p on osteoblast differentiation. Mechanistic explorations revealed that miR-196b-5p directly targeted semaphorin 3a (Sema3a) and inhibited Wnt/β-catenin signaling. SEMA3A attenuated the impaired osteogenesis induced by miR-196b-5p. Osteoblast-specific miR-196b transgenic mice showed significant reduction of bone mass. Trabecular osteoblasts were reduced and bone formation was suppressed, whereas osteoclasts, marrow adipocytes, and serum levels of bone resorption markers were increased in the transgenic mice. The osteoblastic progenitor cells from the transgenic mice had decreased SEMA3A levels and exhibited retarded osteogenic differentiation, whereas those marrow osteoclastic progenitors exhibited enhanced osteoclastogenic differentiation. miR-196b-5p and SEMA3A oppositely regulated the expression of receptor activator of nuclear factor-κB ligand and osteoprotegerin. The calvarial osteoblastic cells expressing the transgene promoted osteoclastogenesis, whereas the osteoblasts overexpressing Sema3a inhibited it. Finally, in vivo transfection of miR-196b-5p inhibitor to the marrow reduced ovariectomy-induced bone loss in mice. Our study has identified that miR-196b-5p plays a key role in osteoblast and osteoclast differentiation and regulates bone homeostasis. Inhibition of miR-196b-5p may be beneficial for amelioration of osteoporosis. © 2023 American Society for Bone and Mineral Research (ASBMR).</p>\u0000 </div>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 8","pages":"1175-1191"},"PeriodicalIF":6.2,"publicationDate":"2023-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5768383","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}