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MiR-144-5p and miR-21-5p do not drive bone disease in a mouse model of type 1 diabetes mellitus MiR-144-5p 和 miR-21-5p 不会导致 1 型糖尿病小鼠模型出现骨病
IF 3.8
JBMR Plus Pub Date : 2024-04-06 DOI: 10.1093/jbmrpl/ziae036
S. Daamouch, Matthias Blüher, David Carro Vázquez, Matthias Hackl, L. Hofbauer, M. Rauner
{"title":"MiR-144-5p and miR-21-5p do not drive bone disease in a mouse model of type 1 diabetes mellitus","authors":"S. Daamouch, Matthias Blüher, David Carro Vázquez, Matthias Hackl, L. Hofbauer, M. Rauner","doi":"10.1093/jbmrpl/ziae036","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae036","url":null,"abstract":"Abstract The increased risk of fractures in patients with type 1 diabetes mellitus (T1DM) is nowadays well recognized. However, the exact mechanism of action of diabetic bone disease has not been fully elucidated. MicroRNAs (miRNAs) are gene regulators that operate post-transcriptionally and have been implicated in the development of various metabolic disorders including T1DM. Previous studies have implicated a role for miR-144-5p and miR-21-5p, which are involved in controlling oxidative stress by targeting Nrf2, in T1DM. To date, it is unclear whether miR-144-5p and miR-21-5p affect bone health in T1DM. Thus, this study aimed to investigate the influence of miR-144-5p and miR-21-5p knockdown in the development of bone disease in T1DM male mice. Therefore, T1DM was induced in 10-wk-old male mice using streptozotocin (STZ). One week later, after development of hyperglycemia, antagomir-144-5p and antagomir-21-5p or their non-targeting control were administered at 10 mg/kg BW once a week until the end of the experiment. At 14 wk of age, glucose levels, bone, and fat mass were analyzed. The results revealed that treating T1DM male mice with antagomir-144-5p and antagomir-21-5p did not protect against diabetes development or bone loss, despite the successful downregulation of the miRNAs and the normalization of Nrf2 mRNA levels in bone tissue. Histological and serological parameters of bone formation or resorption were not altered by the antagomir treatment. Finally, we measured the expression of miRNA-144-5p or miRNA-21-5p in the serum of 30 individuals with T1DM and compared them to non-diabetic controls, but did not find an altered expression of either miRNA. In conclusion, the knockdown of miR-144-5p and miR-21-5p does not affect STZ-induced diabetes development or loss of bone mass in male mice. However, it does normalize expression of the anti-oxidant factor Nrf2 in diabetic bone tissue.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140735354","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}
引用次数: 0
Muscle density, but not size, is independently associated with cognitive health in older adults with hip fractures 肌肉密度(而非大小)与髋部骨折老年人的认知健康独立相关
IF 3.8
JBMR Plus Pub Date : 2024-04-02 DOI: 10.1093/jbmrpl/ziae047
Y. Ge, Qian You, Feng Gao, Gang Liu, Ling Wang, Bo Li, M. Tian, Minghui Yang, Xinbao Wu
{"title":"Muscle density, but not size, is independently associated with cognitive health in older adults with hip fractures","authors":"Y. Ge, Qian You, Feng Gao, Gang Liu, Ling Wang, Bo Li, M. Tian, Minghui Yang, Xinbao Wu","doi":"10.1093/jbmrpl/ziae047","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae047","url":null,"abstract":"Abstract Emerging evidence indicates a complex interplay between skeletal muscle and cognitive function. Despite the known differences between muscle quantity and quality, which can be measured via computed tomography (CT), the precise nature of their associations with cognitive performance remain underexplored. To investigate the links between muscle size and density and cognitive impairment (CI) in the older adults with hip fractures, we conducted a post hoc, cross-sectional analysis within a prospective cohort study on 679 patients with hip fractures over 65. Mini-Mental State Examination (MMSE) and routine hip CT imaging were utilized to assess cognition function and muscle characteristics in older adults with hip fractures. The CT scans provided data on cross-sectional area and attenuation for the gluteus maximus (G.MaxM) and the combined gluteus medius and minimus (G.Med/MinM). Participants were categorized into CI and non-CI groups based on education levels and MMSE scores. Multivariate logistic regressions, propensity score (PS) methods, and subgroup analysis were employed to analyze associations and validate findings. This study included 123 participants (81.6 ± 6.8 years, 74% female) with CI and 556 participants (78.5 ± 7.7 years, 72% female) without. Compared to the non-CI group, muscle parameters, especially density, were significantly lower in the CI group. Specifically, G.Med/Min muscle density, but not size was robustly associated with CI (odds ratio (OR) = 0.77, 95% confidence interval = 0.62–0.96, P = 0.02), independent of other medical situations. Sensitivity analysis corroborated that G.Med/Min muscle density was consistently lower in the CI group than the non-CI group, as evidenced in the PS matched (P = 0.024) and weighted cohort (P = 0.033). Enhanced muscle parameters, particularly muscle density in the G.Med/MinM muscle, correlate with a lower risk of CI. Muscle density demonstrates a stronger association with cognitive performance than muscle size, highlighting its potential as a key focus in future cognitive health research.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140755409","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}
引用次数: 0
Estradiol induces bone osteolysis in triple-negative breast cancer via its membrane-associated receptor ERα36. 雌二醇通过其膜相关受体ERα36诱导三阴性乳腺癌骨溶解。
IF 3.8
JBMR Plus Pub Date : 2024-03-26 eCollection Date: 2024-05-01 DOI: 10.1093/jbmrpl/ziae041
D Joshua Cohen, Cydney D Dennis, Jingyao Deng, Barbara D Boyan, Zvi Schwartz
{"title":"Estradiol induces bone osteolysis in triple-negative breast cancer via its membrane-associated receptor ERα36.","authors":"D Joshua Cohen, Cydney D Dennis, Jingyao Deng, Barbara D Boyan, Zvi Schwartz","doi":"10.1093/jbmrpl/ziae041","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae041","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is thought to be an estradiol-independent, hormone therapy-resistant cancer because of lack of estrogen receptor alpha 66 (ERα66). We identified a membrane-bound splice variant, ERα36, in TNBC cells that responds to estrogen (E<sub>2</sub>) and may contribute to bone osteolysis. We demonstrated that the MDA-MB-231 TNBC cell line, which expresses ERα36 similarly to MCF7 cells, is responsive to E<sub>2</sub>, forming osteolytic tumors in vivo. MDA-MB-231 cells activate osteoclasts in a paracrine manner. Conditioned media (CM) from MDA-MB-231 cells treated with bovine serum albumin-bound E<sub>2</sub> (E<sub>2</sub>-BSA) increased activation of human osteoclast precursor cells; this was blocked by addition of anti-ERα36 antibody to the MDA-MB-231 cultures. Osteoclast activation and bone resorption genes were elevated in RAW 264.7 murine macrophages following treatment with E<sub>2</sub>-BSA-stimulated MDA-MB-231 CM. E<sub>2</sub> and E<sub>2</sub>-BSA increased phospholipase C (PLC) and protein kinase C (PKC) activity in MDA-MB-231 cells. To examine the role of ERα36 signaling in bone osteolysis in TNBC, we used our bone-cancer interface mouse model in female athymic homozygous Foxn1<sup>nu</sup> mice. Mice with MDA-MB-231 tumors and treated with tamoxifen (TAM), E<sub>2</sub>, or TAM/E<sub>2</sub> exhibited increased osteolysis, cortical bone breakdown, pathologic fracture, and tumor volume; the combined E<sub>2</sub>/TAM group also had reduced bone volume. These results suggest that E<sub>2</sub> increased osteolytic lesions in TNBC through a membrane-mediated PLC/PKC pathway involving ERα36, which was enhanced by TAM, demonstrating the role of ERα36 and its membrane-associated signaling pathway in bone tumors. This work suggests that ERα36 may be a potential therapeutic target in patients with TNBC.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11032217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140866169","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}
引用次数: 0
Decomposing and simplifying fracture risk assessment tool 分解和简化骨折风险评估工具
IF 3.8
JBMR Plus Pub Date : 2024-03-23 DOI: 10.1093/jbmrpl/ziae039
Chia-Chun Li, I. Liu, Tien-Tsai Cheng, Fu-Wen Liang, Zih‐Jie Sun, Yin-Fan Chang, Chin-Sung Chang, Yi-Ching Yang, Tsung-Hsueh Lu, Li-Chieh Kuo, Chih-Hsing Wu
{"title":"Decomposing and simplifying fracture risk assessment tool","authors":"Chia-Chun Li, I. Liu, Tien-Tsai Cheng, Fu-Wen Liang, Zih‐Jie Sun, Yin-Fan Chang, Chin-Sung Chang, Yi-Ching Yang, Tsung-Hsueh Lu, Li-Chieh Kuo, Chih-Hsing Wu","doi":"10.1093/jbmrpl/ziae039","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae039","url":null,"abstract":"\u0000 The Fracture Risk Assessment tool (FRAX®) is a widely utilized country-specific calculator for identifying individuals with high fracture risk; its score is calculated from 12 variables, but its formulation is not publicly disclosed. We aimed to decompose and simplify the FRAX® by utilizing a nationwide community survey database as a reference module for creating a local assessment tool for osteoporotic fracture community screening in any country. Participants (n = 16 384: predominantly women (75%); mean age = 64.8 years) were enrolled from the Taiwan OsteoPorosis Survey, a nationwide cross-sectional community survey database collected from 2008–2011. We identified 11 other clinical risk factors from the health questionnaires. Bone mineral density (BMD) was assessed via dual-energy X-ray absorptiometry in a mobile DXA vehicle, and 10-year fracture risk scores, including major osteoporotic fracture (MOF) and hip fracture (HF) risk scores, were calculated using the FRAX®. The mean femoral neck BMD was 0.7 ± 0.1 g/cm2, the T-score was -1.9 ± 1.2, the MOF was 8.9 ± 7.1%, and the HF was 3.2 ± 4.7%. Following FRAX® decomposition with multiple linear regression, the adjusted R2 values were 0.9206 for MOF and 0.9376 for HF when BMD was included and 0.9538 for MOF and 0.9554 for HF when BMD was excluded. The FRAX® demonstrated better prediction for women and younger individuals than for men and elderly individuals after sex and age stratification analysis. Excluding femoral neck BMD, age, sex, and previous fractures emerged as three primary clinical risk factors for simplified FRAX® according to the decision tree analysis in this study population. The adjusted R2 values for the simplified country-specific FRAX® incorporating three premier clinical risk factors were 0.8210 for MOF and 0.8528 for HF. After decomposition, the newly simplified module provides a straightforward formulation for estimating 10-year fracture risk, even without femoral neck BMD, making it suitable for community or clinical osteoporotic fracture risk screening.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140211185","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}
引用次数: 0
Week-by-week changes in serum levels of bone-related circulating microRNAs and bone turnover markers. 骨相关循环 microRNA 和骨转换标志物的血清水平逐周变化。
IF 3.8
JBMR Plus Pub Date : 2024-03-22 eCollection Date: 2024-05-01 DOI: 10.1093/jbmrpl/ziae035
Patryk Zarecki, Fatma Gossiel, Johannes Grillari, Miguel Debono, Matthias Hackl, Richard Eastell
{"title":"Week-by-week changes in serum levels of bone-related circulating microRNAs and bone turnover markers.","authors":"Patryk Zarecki, Fatma Gossiel, Johannes Grillari, Miguel Debono, Matthias Hackl, Richard Eastell","doi":"10.1093/jbmrpl/ziae035","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae035","url":null,"abstract":"<p><p>MicroRNAs are involved in post-transcriptional regulation of gene expression. Due to their regulatory role, microRNAs are differently expressed during specific conditions in healthy and diseased individuals, so microRNAs circulating in the blood could be used as diagnostic and prognostic biomarkers for various diseases and conditions. We want to investigate the variability of circulating microRNAs and bone turnover markers in weekly time intervals in older women. In a single-site longitudinal study, a panel of 19 bone-related miRNAs was measured using the osteomiR RT-qPCR assay in serum samples of 35 postmenopausal women divided into 3 groups: healthy controls (<i>n</i> = 12), low BMD (<i>n</i> = 14), and vertebral fractures (<i>n</i> = 9). Blood samples for measurement of CTX, PINP, OC, and bone ALP were collected once per week for 8 weeks at 9:00 AM after overnight fasting. Serum samples from all participants were analyzed for 19 microRNA bone biomarkers and 4 bone turnover markers over 8 weeks. We analyzed the data using a mixed model analysis of variance and found no significant changes between week-by-week time points in any of the groups. To estimate intraindividual variability between weekly time points, we have calculated the median coefficient of variation (CV). This was between 28.4% and 80.2% for microRNA, with an assay CV of 21.3%. It was between 8.5% and 15.6% for bone turnover markers, with an assay CV of 3.5% to 6.5%. The intraindividual variability was similar between groups. Circulating microRNAs measured in serum had a higher weekly intraindividual variability than bone turnover markers due in part to a higher assay CV.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11008742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140859624","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}
引用次数: 0
The Anti-HIV Drug Abacavir stimulates β-catenin activity in osteoblast lineage cells 抗艾滋病毒药物阿巴卡韦刺激成骨细胞系细胞中β-catenin的活性
IF 3.8
JBMR Plus Pub Date : 2024-03-19 DOI: 10.1093/jbmrpl/ziae037
Arnold Z. Olali, Jennillee Wallace, Hemil Gonzalez, K. A. Carpenter, Niyati Patel, Lee C Winchester, A. Podany, Ishwarya Venkatesh, S. Narasipura, Lena Al-Harthi, Ryan D Ross
{"title":"The Anti-HIV Drug Abacavir stimulates β-catenin activity in osteoblast lineage cells","authors":"Arnold Z. Olali, Jennillee Wallace, Hemil Gonzalez, K. A. Carpenter, Niyati Patel, Lee C Winchester, A. Podany, Ishwarya Venkatesh, S. Narasipura, Lena Al-Harthi, Ryan D Ross","doi":"10.1093/jbmrpl/ziae037","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae037","url":null,"abstract":"\u0000 Bone mineral density (BMD) loss in people living with HIV (PLWH) occurs with the initiation of combined antiretroviral therapy (cART), particularly with tenofovir disoproxil fumarate (TDF) containing cART. Switching from TDF to abacavir (ABC) or dolutegravir (DTG) leads to increased BMD. Whether BMD gains are due to cessation of TDF or anabolic effects of ABC or DTG is unclear. We investigated the effects of ABC and DTG on osteoblast lineage cells in vitro and in vivo. Primary human osteoblasts and male C57BL/6 mice were treated with individual antiretrovirals (ARVs) or a combination of ABC/DTG/lamivudine (3TC). Nearly all ARVs and cART inhibited osteogenic activity in vitro. Due to the importance of Wnt/β-catenin in bone formation, we further investigated ARV effects on the Wnt/β-catenin pathway. ABC, alone and as part of ABC/DTG/3TC, increased osteoblastic β-catenin activity as indicated by increased TOPFlash activity, hypo-phosphorylated (active) β-catenin staining, and β-catenin targeted gene expression. Mice treated with TDF had decreased lumbar spine BMD and trabecular connectivity density in the vertebrae, while those treated with ABC/DTG/3TC reduced cortical area and thickness in the femur. Mice treated with ABC alone had no bone structural changes, increased circulating levels of the bone formation marker, P1NP, and elevated expression of the Wnt/β-catenin target gene, Lef1, in osteocyte enriched samples. Further, bones from ARV-treated mice were isolated to evaluate ARV distribution. All ARVs were detected in the bone tissue, which was inclusive of bone marrow, but when bone marrow was removed, only TDF, ABC, and DTG were detected at ~0.1% of the circulating levels. Overall, our findings demonstrate that ABC activates Wnt/β-catenin signaling, but whether this leads to increased bone formation requires further study. Assessing the impact of ARVs on bone is critical to informing ARV selection and/or discovery of regimens that do not negatively impact the skeleton.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140229697","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}
引用次数: 0
Discordant responses of bone formation and absorption markers in Japanese infants with vitamin D deficiency: a comprehensive matched case–control study 维生素 D 缺乏症日本婴儿骨形成和吸收指标的不一致反应:一项全面的匹配病例对照研究
IF 3.8
JBMR Plus Pub Date : 2024-03-18 DOI: 10.1093/jbmrpl/ziae033
Keigo Takahashi, Kazushige Ikeda, Kaori Hara-Isono, Akihisa Nitta, Nobuhiko Nagano, T. Arimitsu
{"title":"Discordant responses of bone formation and absorption markers in Japanese infants with vitamin D deficiency: a comprehensive matched case–control study","authors":"Keigo Takahashi, Kazushige Ikeda, Kaori Hara-Isono, Akihisa Nitta, Nobuhiko Nagano, T. Arimitsu","doi":"10.1093/jbmrpl/ziae033","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae033","url":null,"abstract":"\u0000 Vitamin D deficiency during infancy has been associated with increased bone turnover rate and bone mineral loss. However, few studies have examined bone turnover markers (BTMs) for both bone formation and resorption in infants with vitamin D deficiency. Here, we analyzed serum concentrations of 25(OH)D, intact parathormone (iPTH), and BTMs including total alkaline phosphatase (ALP), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), and serum type I collagen N-telopeptide (NTx) as well as basic clinical characteristics of 456 infants (626 samples) aged less than 12 months born at Saitama City Hospital, Japan (latitude 35.9° North) between January 2021 and December 2022. 116 infants (147 samples) were classified as having vitamin D deficiency (25(OH)D < 12.0 ng/mL), and 340 infants (479 samples) had sufficient vitamin D levels (25(OH)D ≥ 12.0 ng/mL). In addition to 25(OH)D and ALP, both TRACP-5b and sNTx were measured in 331 infants (418 samples), while 90 infants (105 samples) had only TRACP-5b only measured and 101 infants (103 samples) had only sNTx measured. Statistical comparison of 104 subjects each in the vitamin D deficiency and sufficiency groups after matching for the background characteristics revealed that the vitamin D deficiency group had significantly higher levels of ALP and iPTH compared with the sufficiency group (p = <0.0001, 0.0012, respectively). However, no significant differences were found in TRACP-5b and NTx levels between the two groups (p = 0.19, 0.08, respectively). Our findings suggest discordant responses between bone formation and resorption markers in subclinical vitamin D deficiency during infancy.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140234042","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}
引用次数: 0
Molecular and functional mapping of Plekhm1-Rab7 interaction in osteoclasts 破骨细胞中Plekhm1-Rab7相互作用的分子和功能图谱
IF 3.8
JBMR Plus Pub Date : 2024-03-12 DOI: 10.1093/jbmrpl/ziae034
Bhaba K Das, Tarun Minocha, Mikaela D. Kunika, Aarthi Kannan, Ling Gao, S. Mohan, Weirong Xing, Kottayil I Varughese, Haibo Zhao
{"title":"Molecular and functional mapping of Plekhm1-Rab7 interaction in osteoclasts","authors":"Bhaba K Das, Tarun Minocha, Mikaela D. Kunika, Aarthi Kannan, Ling Gao, S. Mohan, Weirong Xing, Kottayil I Varughese, Haibo Zhao","doi":"10.1093/jbmrpl/ziae034","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae034","url":null,"abstract":"\u0000 Mutations in PLEKHM1 cause osteopetrosis in humans and rats. The germline and osteoclast conditional deletions of Plekhm1 gene in mice lead to defective osteoclast bone resorption and increased trabecular bone mass without overt abnormalities in other organs. As an adaptor protein, PLEKHM1 interacts with the key lysosome regulator small GTPase RAB7 via its C-terminal RUBICON homologous (RH) domain. In this study, we have conducted a structural-functional study of the PLEKHM1 RH domain and RAB7 interaction in osteoclasts in vitro. The single mutations of the key residues in the Plekhm1 RH predicted from the crystal structure of the RUBICON RH domain and RAB7 interface failed to disrupt the Plekhm1-Rab7 binding, lysosome trafficking, and bone resorption. The compound alanine mutations at Y949-R954 and L1011-I1018 regions decreased Plekhm1 protein stability and Rab7-binding, respectively, thereby attenuated lysosome trafficking and bone resorption in osteoclasts. In contrast, the compound alanine mutations at R1060-Q1068 region were dispensable for Rab7-binding and Plekhm1 function in osteoclasts. These results indicate that the regions spanning Y949-R954 and L1011-I1018 of Plekhm1 RH domain are functionally important for Plekhm1 in osteoclasts and offer the therapeutical targets for blocking bone resorption in treatment of osteoporosis and other metabolic bone diseases.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140250016","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}
引用次数: 0
Local application of zoledronate inhibits early bone resorption and promotes bone formation. 局部使用唑来膦酸钠可抑制早期骨吸收,促进骨形成。
IF 3.8
JBMR Plus Pub Date : 2024-03-09 eCollection Date: 2024-05-01 DOI: 10.1093/jbmrpl/ziae031
Ming-Kai Hsieh, Chi-Yun Wang, Fu-Cheng Kao, Hui-Ting Su, Mei-Feng Chen, Tsung-Ting Tsai, Po-Liang Lai
{"title":"Local application of zoledronate inhibits early bone resorption and promotes bone formation.","authors":"Ming-Kai Hsieh, Chi-Yun Wang, Fu-Cheng Kao, Hui-Ting Su, Mei-Feng Chen, Tsung-Ting Tsai, Po-Liang Lai","doi":"10.1093/jbmrpl/ziae031","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae031","url":null,"abstract":"<p><p>Nonunion resulting from early bone resorption is common after bone transplantation surgery. In these patients, instability or osteoporosis causes hyperactive catabolism relative to anabolism, leading to graft resorption instead of fusion. Systemic zoledronate administration inhibits osteoclastogenesis and is widely used to prevent osteoporosis; however, evidence on local zoledronate application is controversial due to osteoblast cytotoxicity, uncontrolled dosing regimens, and local release methods. We investigated the effects of zolendronate on osteoclastogenesis and osteogenesis and explored the corresponding signaling pathways. In vitro cytotoxicity and differentiation of MC3T3E1 cells, rat bone marrow stromal cells (BMSCs) and preosteoclasts (RAW264.7 cells) were evaluated with different zolendronate concentrations. In vivo bone regeneration ability was tested by transplanting different concentrations of zolendronate with β-tricalcium phosphate (TCP) bone substitute into rat femoral critical-sized bone defects. In vitro<i>,</i> zolendronate concentrations below 2.5 × 10<sup>-7</sup> M did not compromise viability in the three cell lines and did not promote osteogenic differentiation in MC3T3E1 cells and BMSCs. In RAW264.7 cells, zoledronate inhibited extracellular regulated protein kinases and c-Jun n-terminal kinase signaling, downregulating c-Fos and NFATc1 expression, with reduced expression of fusion-related dendritic cell‑specific transmembrane protein and osteoclast-specific Ctsk and tartrate-resistant acid phosphatase (. In vivo<i>,</i> histological staining revealed increased osteoid formation and neovascularization and reduced fibrotic tissue with 500 μM and 2000 μM zolendronate. More osteoclasts were found in the normal saline group after 6 weeks, and sequential osteoclast formation occurred after zoledronate treatment, indicating inhibition of bone resorption during early callus formation without inhibition of late-stage bone remodeling. In vivo<i>,</i> soaking β-TCP artificial bone with 500 μM or 2000 μM zoledronate is a promising approach for bone regeneration, with potential applications in bone transplantation.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11008729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140865197","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}
引用次数: 0
Defining the imaging diagnostic criteria for adult chronic non-bacterial osteitis. 确定成人慢性非细菌性骨炎的影像诊断标准。
IF 3.8
JBMR Plus Pub Date : 2024-03-08 eCollection Date: 2024-05-01 DOI: 10.1093/jbmrpl/ziae024
Ashna I E Ramautar, Ana Navas, Elizabeth M Winter, Herman M Kroon, Frits Smit, Dennis Vriens, Neveen A T Hamdy, Natasha M Appelman-Dijkstra
{"title":"Defining the imaging diagnostic criteria for adult chronic non-bacterial osteitis.","authors":"Ashna I E Ramautar, Ana Navas, Elizabeth M Winter, Herman M Kroon, Frits Smit, Dennis Vriens, Neveen A T Hamdy, Natasha M Appelman-Dijkstra","doi":"10.1093/jbmrpl/ziae024","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae024","url":null,"abstract":"<p><p>Osteitis of the sternocostoclavicular (SCC) region, referred to as sternocostoclavicular hyperostosis (SCCH), is the clinical expression of chronic non-bacterial osteitis (CNO) in adults with this rare chronic auto-inflammatory disorder of the axial skeleton. The diagnosis is based on distinctive computerized tomography (CT) features of sclerosis and hyperostosis of the SCC region, and local increases in osteoid formation visualized by high radiopharmacon uptake on skeletal scintigraphy but clear radiologic diagnostic criteria are lacking. In a cross-sectional study, CT scans and whole-body skeletal scintigraphy images obtained in 169 patients seen at the Center for Bone Quality of the Leiden University Medical Center between 2008 and 2018 with a suspected diagnosis of CNO of the SCC region were re-evaluated by 2 skeletal radiologists and 2 nuclear physicians. The diagnosis was confirmed in 118 (70%) predominantly female patients (<i>n</i> = 103, 89.2%); median age at first symptoms 45 years (range 20-73). The diagnosis was excluded in the remaining 51 \"non-CNO\" patients. Increased radiopharmacon uptake at the SCC region was observed in 82% CNO patients, with the manubrium sterni having the highest predictive ability to discriminate on both imaging modalities. The prevalence of sclerosis of the clavicles, manubrium and first ribs was significantly higher in CNO patients (<i>P</i> < 0.001). Hyperostosis was not observed in non-CNO patients. 46 CNO versus only 2 non-CNO patients had costoclavicular ligament calcification. Our findings identify CT scan features of sclerosis and hyperostosis of manubrium sterni, medial end of clavicles and first ribs, and calcification of costoclavicular ligaments, associated with increased tracer uptake on skeletal scintigraphy at the SCC region, specifically manubrium sterni, as well-defined imaging diagnostic criteria for adult CNO. Pitfalls encountered in the diagnosis of CNO are highlighted. These defined imaging diagnostic criteria for adult CNO should facilitate the diagnosis of this rare auto-inflammatory bone disease across the spectrum of its early to late stages.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11008733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140869914","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}
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