JBMR Plus最新文献

{"title":"A protocol for the prospective study of urinary cadmium with risk of fracture, bone loss, and muscle loss","authors":"Christopher de la Bastide, Lissa Soares, L. Lui, James Harrington, Peggy Cawthon, Eric Orwoll, Deborah Kado, Jaymie Meliker","doi":"10.1093/jbmrpl/ziad006","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad006","url":null,"abstract":"\u0000 Cadmium (Cd) is a heavy metal and natural element found in soil and crops with increasing concentrations linked to phosphate fertilizers and sewage sludge applied to crop lands. A large fraction of older U.S men and woman have documented Cd exposure. Cd exposure has proven health concerns such as risk of lung cancer from inhalation and impaired renal function, however, growing evidence suggests it also influences bone and muscle health. Given that low levels of Cd could affect bone and muscle, we have designed prospective studies using the two largest and most detailed U.S. studies of bone health in older men and women: The Osteoporotic Fractures in Men (MrOS) Study and the Study of Osteoporotic Fractures (SOF). We are investigating the association of urinary cadmium (U-Cd), as a surrogate for long term cadmium exposure, with bone and muscle health. Building off suggestive evidence from mechanistic and cross-sectional studies, this will be the first well-powered prospective study of incident fracture outcomes, bone loss, and muscle loss in relation to U-Cd, an established biomarker of long-term Cd exposure. The following is a proposed protocol for the intended study; if successful the proposed studies could be influential in directing future U.S policy to decrease Cd exposure in the U.S population similar to recent policies adopted by the European Union to limit Cd in fertilizers.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"44 24","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139387003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advanced Glycation End Products Are Not Associated With Bone Mineral Density, Trabecular Bone Score and Bone Turnover Markers in Adults With and Without Type 1 Diabetes: A Cross-Sectional Study","authors":"J. Coll, Anne-Frédérique Turcotte, William D Leslie, Laëtitia Michou, S. J. Weisnagel, Fabrice Mac-Way, Caroline Albert, Claudie Berger, Suzanne N Morin, Rémi Rabasa-Lhoret, Claudia Gagnon","doi":"10.1093/jbmrpl/ziad018","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad018","url":null,"abstract":"\u0000 It is unclear if advanced glycation end products (AGEs) are involved in the bone fragility of type 1 diabetes (T1D). We evaluated whether skin AGEs by skin autofluorescence and serum AGEs (pentosidine, carboxymethyl-lysine [CML]) are independently associated with BMD by DXA (lumbar spine, hip, distal radius), trabecular bone score (TBS), serum bone turnover markers (BTMs: C-terminal crossed-linked telopeptide of type 1 collagen, CTX; procollagen type 1 N-terminal propeptide, P1NP; osteocalcin), and sclerostin in participants with and without T1D. Linear regression models were used, with interaction terms to test effect modification by T1D status. In participants with T1D, correlations between skin and serum AGEs as well as between AGEs and 3-year HbA1C were evaluated using Spearman’s correlations. Data are mean±SD or median(interquartile range). We included individuals who participated in a cross-sectional study and had BMD and TBS assessment (106 T1D/65 controls, 53.2% women, age 43±15 years, BMI 26.6±5.5 kg/m2). Participants with T1D had diabetes for 27.6±12.3 years, a mean 3-year HbA1C of 7.5±0.9% and skin AGEs of 2.15±0.54 arbitrary units. A subgroup of 65 T1D/57 controls had BTMs and sclerostin measurements, and those with T1D also had serum pentosidine (16.8[8.2-32.0] ng/mL) and CML [48.0±16.8] ng/mL) measured. Femoral neck BMD, TBS, and BTMs were lower while sclerostin levels were similar in participants with T1D vs controls. T1D status did not modify the associations between AGEs and bone outcomes. Skin AGEs were significantly associated with total hip and femoral neck BMD, TBS, BTMs, and sclerostin before, but not after adjustment for confounders. Serum AGEs were not associated with any bone outcome. There were no significant correlations between skin and serum AGEs, or between AGEs and 3-year HbA1C. In conclusion, skin and serum AGEs are not independently associated with BMD, TBS, BTMs, and sclerostin in participants with relatively well-controlled T1D and participants without diabetes.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"57 7","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139450656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence of osteoporosis, sarcopenia, and high falls risk in healthy community-dwelling Thai older adults: a nationwide cross-sectional study","authors":"A. Asavamongkolkul, N. Adulkasem, P. Chotiyarnwong, Ekasame Vanitcharoenkul, Chandhanarat Chandhanayingyong, Panai Laohaprasitiporn, Krabkaew Soparat, A. Unnanuntana","doi":"10.1093/jbmrpl/ziad020","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad020","url":null,"abstract":"\u0000 Thailand has transitioned from an aging society to an aged society, which implies that the prevalence of age-related disorders will increase; however, epidemiological data specific to the prevalence of age-related degenerative musculoskeletal disorders among Thai older adults remain limited. Accordingly, the aim of this study was to investigate the prevalence of age-related musculoskeletal diseases, including osteoporosis, sarcopenia, and high falls risk among healthy community-dwelling Thai older adults. This cross-sectional nationwide study enrolled Thai adults aged ≥60 years from 2 randomly selected provinces from each of the 6 regions of Thailand via stratified multistage sampling during March 2021 to August 2022. All enrolled participants were evaluated for bone mineral density, skeletal muscle mass, grip strength, and gait speed. Osteoporosis was diagnosed according to the World Health Organization definition, and sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia 2019 criteria. Falls risk was determined using the self-rated Fall Risk Questionnaire (FRQ). A total of 2991 eligible participants were recruited. The mean age of participants was 69.2 ± 6.5 years (range: 60–107), and 63.1% were female. The prevalence of osteoporosis, sarcopenia, and high falls risk was 29.7%, 18.1%, and 38.5%, respectively. Approximately one-fifth of subjects (19.1%) had at least 2 of 3 risk factors (i.e., osteoporosis, sarcopenia, and high falls risk) for sustaining a fragility fracture, and 3.4% had all three risk factors. In conclusion, the results of this study revealed a high and increasing prevalence of osteoporosis, sarcopenia, and high falls risk in healthy community-dwelling Thai older adults. Since these conditions are all major risk factors for fragility fracture, modification of Thailand’s national healthcare policy is urgently needed to address the increasing prevalence of these conditions among healthy community-dwelling older adults living in Thailand.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"30 10","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139386472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Burosumab versus conventional therapy in children with X-linked hypophosphatemia: results of the open-label, phase 3 extension period","authors":"Leanne M. Ward, Wolfgang Högler, Francis H. Glorieux, A. Portale, Michael P. Whyte, C. Munns, Ola Nilsson, Jill H Simmons, Raja Padidela, Noriyuki Namba, H. Cheong, Etienne Sochett, Koji Muroya, Hiroyuki Tanaka, P. Pitukcheewanont, G. Gottesman, Andrew Biggin, Farzana Perwad, Angel Chen, J. Lawrence Merritt, Erik A. Imel","doi":"10.1093/jbmrpl/ziad001","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad001","url":null,"abstract":"\u0000 In a randomized, open-label phase 3 study of 61 children 1–12 years old with X-linked hypophosphatemia (XLH) previously treated with conventional therapy, changing to bi-weekly (Q2W) burosumab for 64 weeks improved phosphate metabolism, radiographic rickets, and growth compared with conventional therapy. In this open-label extension period (weeks 64–88), 21 children continued burosumab Q2W at the previous dose or crossed over from conventional therapy to burosumab starting at 0.8 mg/kg Q2W and had continued clinical radiographic assessments through week 88. Efficacy endpoints and safety observations were summarized descriptively for the treatment groups (burosumab continuation, n = 6; crossover, n = 15). At week 88 compared with baseline, improvements in the following outcomes were observed in the burosumab continuation and crossover groups, respectively: mean (SD) RGI-C rickets total score (primary outcome), +2.11 (0.27) and + 1.89 (0.35); mean (SD) RGI-C lower limb deformity score, +1.61 (0.91) and + 0.73 (0.82), and mean (SD) height Z-score + 0.41 (0.50) and + 0.08 (0.34). Phosphate metabolism normalized rapidly in the crossover group and persisted in the continuation group. Mean (SD) serum ALP decreased from 169% (43%) of the upper limit of normal (ULN) at baseline to 126% (51%) at week 88 in the continuation group, and from 157% (33%) of the ULN at baseline to 111% (23%) at week 88 in the crossover group. During the extension period, treatment-emergent adverse events (AEs) were reported in all six children in the burosumab continuation group and in 14/15 children in the cross-over group. AE profiles in the randomized and extension periods were similar, with no new safety signals identified. Thus, improvements from baseline in radiographic rickets continued in the extension period among children with XLH who remained on burosumab. Children who crossed over from conventional therapy to burosumab demonstrated rapid improvement in phosphate metabolism and improved rickets healing over the ensuing 22 weeks.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"77 7","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139387189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Collagen mutation and age contribute to differential craniofacial phenotypes in mouse models of osteogenesis imperfecta","authors":"Hsiao H Sung, Wyatt Spresser, Joseph P Hoffmann, Zongrui Dai, Peter M Van der Kraan, M. Caird, Esmeralda Blaney Davidson, K. Kozloff","doi":"10.1093/jbmrpl/ziad004","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad004","url":null,"abstract":"\u0000 Craniofacial and dentoalveolar abnormalities are present in all types of Osteogenesis Imperfecta (OI). Mouse models of the disorder are critical to understanding these abnormalities and underlying OI pathogenesis. Previous studies on severely affected OI mice report a broad spectrum of craniofacial phenotypes, exhibiting some similarities to the human disorder. Brtl/+ and G610c/+ are moderately severe and mild type IV OI, respectively. Little is known about the aging effects on the craniofacial bones of these models and their homology to human OI. This study aimed to analyze the Brtl/+ and G610c/+ craniofacial morphometries during aging to establish suitability for further OI craniofacial bone intervention studies. We performed morphological measurements on the micro-CT scanned heads of 3-week-old, 3-month-old, and 6-month-old female Brtl/+ and G610c/+ mice. We observed that Brtl/+ skulls are shorter in length than WT (p < 0.05), whereas G610c/+ skulls are similar in length to their WT counterparts. Brtl/+ mice exhibit alveolar bone with a porotic-like appearance that is not observed in G610c/+. As they age, Brtl/+ mice show severe bone resorption in both the maxilla and mandible (p < 0.05). In contrast, G610c/+ mice experience mandibular resorption consistently across all ages, but maxillary resorption is only evident at 6 months (p < 0.05). Western blot shows high osteoclastic activities in the Brtl/+ maxilla. Both models exhibit delayed pre-functional eruptions of the third molars (p < 0.05), similar to those observed in some bisphosphonate-treated OI subjects. Our study shows that the Brtl/+ and G610c/+ mice display clear features found in type IV OI patients; both show age-related changes in craniofacial growth phenotype. Therefore, understanding the craniofacial features of these models and how they age will allow us to select the most accurate mouse model, mouse age, and bone structure for the specific craniofacial bone treatment of differing OI groups.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"38 8","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139385780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"18F-sodium fluoride PET-CT visualizes disease activity in adult chronic nonbacterial osteitis (CNO)","authors":"A. Leerling, F. Smit, Zita Spӓth, Ana Navas Cañete, L. de Geus-Oei, A. van de Burgt, Olaf M Dekkers, W. van der Bruggen, Natasha M Appelman-Dijkstra, D. Vriens, Elizabeth M Winter","doi":"10.1093/jbmrpl/ziad007","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad007","url":null,"abstract":"\u0000 \u0000 \u0000 Chronic nonbacterial osteitis (CNO) is a rare disease spectrum, which lacks biomarkers for disease activity. Sodium fluoride positron emission tomography ([18F]NaF-PET/CT) is a sensitive imaging tool for bone diseases and yields quantitative data on bone turnover. We evaluate the capacities of [18F]NaF-PET/CT to provide structural and functional assessment in adult CNO.\u0000 \u0000 \u0000 \u0000 Cross-sectional study among 43 adult CNO patients and 16 controls (patients referred for suspected, but not diagnosed as CNO) undergoing [18F]NaF-PET/CT at our expert clinic. Structural features were compared between patients and controls, and maximal standardized uptake values (SUVmax (g/ml)) were calculated for bone lesions, soft tissue/joint lesions, and reference bone. SUVmax was correlated with clinical disease activity in patients.\u0000 \u0000 \u0000 \u0000 Manubrial and costal sclerosis/hyperostosis, and calcification of the costoclavicular ligament emerged core structural features associated with CNO as visualized by [18F]NaF-PET/CT. SUVmax of CNO lesions was higher compared to in-patient reference bone (mean paired difference 11.4, 95%CI9.4–13.5, p < 0.001) and controls (mean difference 12.4, 95%CI9.1–15.8, p < 0.001). Highest SUVmax values were found in soft tissue and joint areas like the costoclavicular ligament and manubriosternal joint, and these correlated with erythrocyte sedimentation rate in patients (correlation coefficient 0.546, p < 0.002).\u0000 \u0000 \u0000 \u0000 [18F]NaF-PET/CT is a promising imaging tool for adult CNO, allowing for detailed structural evaluation of its typical bone, soft-tissue and joint features. At the same time, [18F]NaF-PET/CT yields quantitative bone remodeling data that represent the pathologically increased bone turnover and the process of new bone formation. Further studies should investigate the application of quantified [18F]NaF-uptake as a novel biomarker for disease activity in CNO, and its utility to steer clinical decision-making.\u0000","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"26 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139450722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mer tyrosine kinase regulates bone metabolism, and its deficiency partially ameliorates periodontitis- and ovariectomy-induced bone loss in mice","authors":"Ka-Young Ryu, N. K. Pokhrel, Hye-Jin Jung, Hyo Jeong Kim, Jiwon Seok, Tae-Young Kim, Hyung Joon Kim, Ji Hye Lee, Jae-Young Kim, Yong-Gun Kim, Youngkyun Lee","doi":"10.1093/jbmrpl/ziad014","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad014","url":null,"abstract":"\u0000 Bone homeostasis is maintained by tightly coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts. In the present report, the role of Mer tyrosine kinase (MerTK) in bone metabolism was investigated. The expression of MerTK decreased upon BMP2 stimulation of osteoblast precursors. The femurs of Mertk-deficient mice showed significantly increased bone volume with concomitant increase of bone formation and reduction in bone resorption. These bone phenotypes were attributed to the increased osteoblast differentiation and mineralization accounted by the enhanced β-Catenin and Smad signaling in the absence of MerTK in osteoblast precursors. Although the Mertk-deficient bone marrow macrophages were predisposed to enhanced osteoclast differentiation via augmented Ca2+-NFATc1 signaling, the dramatic increase of Tnfsf11b/Tnfsf11 (Opg/Rankl) ratio in Mertk knockout bones and osteoblast precursors corroborated the reduction of osteoclastogenesis in Mertk deficiency. In ligature-induced periodontitis and ovariectomy models, the bone resorption was significantly attenuated in Mertk-deficient mice compared with wild type control. Taken together, these data indicate novel role of MerTK in bone metabolism and suggest a potential strategy targeting MerTK in treating bone-lytic diseases including periodontitis and osteoporosis.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"63 2","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139385613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Individual trabecula segmentation validation in first- and second-generation high-resolution peripheral computed tomography compared to micro-computed tomography in the distal radius and tibia.","authors":"Andreea Teodora Dinescu, Bin Zhou, Yizhong Jenny Hu, Sanchita Agarwal, Elizabeth Shane, Xiang-Dong Edward Guo","doi":"10.1093/jbmrpl/ziae007","DOIUrl":"10.1093/jbmrpl/ziae007","url":null,"abstract":"<p><p>High-resolution peripheral quantitative computed tomography (HR-pQCT) has been used for in vivo 3D visualization of trabecular microstructure. Second-generation HR-pQCT (HR-pQCT II) has been shown to have good agreement with first generation HR-pQCT (HR-pQCT I). Advanced Individual Trabecula Segmentation (ITS) decomposes the trabecula network into individual plates and rods. ITS based on HR-pQCT I showed a strong correlation to ITS based on micro-computed tomography (μCT) and identified trabecular changes in metabolic bone diseases. ITS based on HR-pQCT II has new potential because of the enhanced resolution but has yet to be validated. The objective of this study was to assess the agreement between ITS based on HR-pQCT I, HR-pQCT II, and μCT to assess the capability of ITS on HR-pQCT images as a tool for studying bone structure. Freshly frozen tibia and radius bones were scanned in the distal region using HR-pQCT I at 82 μm, HR-pQCT II at 60.7 μm, and μCT at 37 μm. Images were registered, binarized, and ITS analysis was performed. Bone volume fraction (pBV/TV, rBV/TV), number density (pTb.N, rTb.N), thickness (pTb.Th, rTb.Th), and plate-to-rod (PR) ratio (pBV/rBV) of trabecular plates and rods were obtained. Paired Student's <i>t</i>-tests with post hoc Bonferroni analysis were used to examine the differences. Linear regression was used to determine the correlation coefficient. The HR-pQCT I parameters were different from the μCT measurements. The HR-pQCT II parameters were different from the μCT measurements except for rTb.N, and the HR-pQCT I parameters were different from the HR-pQCT II measurements except for pTb.Th. The strong correlation between HR-pQCT II and μCT microstructural analysis (R² = 0.55-0.94) suggests that HR-pQCT II can be used to assess changes in plate and rod microstructure and that values from HR-pQCT I can be corrected.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"8 3","pages":"ziae007"},"PeriodicalIF":3.4,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10945717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140174720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chromatin accessibility and epigenetic DNA modifications in CKD osteoblasts: a study of bone and osteoblasts from pediatric patients with chronic kidney disease","authors":"Aline Martin, R. Kawaguchi, Qing Wang, I. Salusky, Renata C Pereira, K. Wesseling-Perry","doi":"10.1093/jbmrpl/ziad015","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad015","url":null,"abstract":"\u0000 Maturation defects are intrinsic features of osteoblast lineage cells in CKD patients. These defects persist ex vivo, suggesting that CKD induces epigenetic changes in bone cells. To gain insights into which signaling pathways contribute to CKD-mediated, epigenetically-driven, impairments in osteoblast maturation, we characterized RNA expression and DNA methylation patterns by RNA-Seq and Methylation Epic in primary osteoblasts from 9 adolescent and young adult dialysis patients with end-stage kidney disease and 3 healthy references. ATAC-Seq was also performed on a subset of osteoblasts. Bone matrix protein expression was extracted from iliac crest and evaluated by proteomics. GSEA analysis was used to establish signaling pathways consistently altered in chromatin accessibility, DNA methylation, and RNA expression patterns. Single genes were suppressed in primary osteoblasts using shRNA and mineralization characterized in vitro. The effect of NFAT signaling suppression was also assessed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) incorporation. We found that signaling pathways critical for osteoblast differentiation were strongly downregulated in CKD osteoblasts. GSEA identified highly significant methylation changes, differential chromatin accessibility, and altered RNA expression in NFAT signaling targets. NFAT inhibition reduced osteoblast proliferation. Combined analysis of osteoblast RNA expression and whole bone matrix composition identified thirteen potential ligand-receptor pairs were identified. In summary, epigenetic changes in CKD osteoblasts associate with altered expression of multiple osteoblast genes and signaling pathways. An increase in NFAT signaling may play a role in impaired CKD osteoblast maturation. Epigenetic changes also associate with an altered bone matrix which may contribute to bone fragility. Further studies are necessary to elucidate the pathways affected by these genetic alterations since elucidating these pathways will be vital to correcting the underlying biology of bone disease in the CKD population.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"5 10","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139385983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripheral canalicular branching is decreased in streptozotocin-induced diabetes and correlates with decreased whole-bone ultimate load and perilacunar elastic work","authors":"Morgan W. Bolger, Tara Tekkey, David H. Kohn","doi":"10.1093/jbmrpl/ziad017","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziad017","url":null,"abstract":"\u0000 Osteocytes are the most abundant cell type in bone, important for mechanosensation, signaling for bone formation, resorption and osteocytes reside in a complex lacuno-canalicular network (OLCN). Osteocyte signaling is reduced under diabetic conditions, and both type 1 and type 2 diabetes lead to reduced bone turnover, perturbed bone composition and increased fracture risk. We hypothesized this reduced bone turnover and altered bone composition with diabetes is associated with reduced OLCN architecture and connectivity. This study aimed to elucidate: 1) the sequence of OLCN changes with diabetes related to bone turnover, and 2) whether changes to the OLCN are associated with tissue composition and mechanical properties. 12–14 week old male C57BL/6 mice were administered streptozotocin at 50 mg/kg for 5 consecutive days to induce hyperglycemia, sacrificed at baseline (BL), or after being diabetic for 3 (D3), 7 (D7) weeks with age-matched (C3, C7) controls (n = 10–12 per group). Mineralized femoral sections were infiltrated with rhodamine, imaged with confocal microscopy, then the OLCN morphology and topology were characterized and correlated against bone histomorphometry, local and whole bone mechanics and composition. D7 mice exhibited a lower number of peripheral branches relative to C7. The total number of canalicular intersections (nodes) was lower in D3 and D7 relative to BL (p < 0.05 for all) and a reduced bone formation rate (BFR) was observed at D7 vs. C7. The number of nodes explained only 15% of BFR, but 45% of Ct.BV/TV, and 31% of ultimate load. The number of branches explained 30% and 22% of the elastic work at the perilacunar and intracortical region, respectively. Collectively, the reduction in OLCN architecture, and association of OLCN measures with bone turnover, mechanics and composition highlights the relevance of the osteocyte and the OLCN, and a potential therapeutic target for treating diabetic skeletal fragility.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"26 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139385996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}