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Background: Osteoporotic fractures (OPF) are fractures that occur with low-energy injuries or during daily activities, representing a serious consequence of osteoporosis (OP). With the worsening of population aging, the number of OPF patients continues to expand, causing a significant burden on families and society. Consequently, it is significant to diagnose and analyze OPF at the molecular level. Objective: The aim of this research was to explore the diagnostic value of miR-32-3p in OPF patients and to exploit new biomarkers for clinical applications. Methods: The miR-32-3p expression level of patients was detected by RT-qPCR. Diagnostic accuracy of miR-32-3p analyzed adopting ROC curve. Additionally, the risk factors correlation with the occurrence of OPF were assessed by logistic analysis. The effect of miR-32-3p on BMSCs was verified by in vitro transfection experiments. Results: miR-32-3p expression was lower in OPF patients than in OP patients. ROC curve implied that miR-32-3p exhibits commendable sensitivity (88.9%) and specificity (75.6%) to differentiate between OP and OPF patients (AUC = 0.905, P < 0.001). Furthermore, miR-32-3p was correlated with the development of OPF and was a risk factor for OPF (P < 0.001). Functional assays revealed that transfection with miR-32-3p mimic could promote proliferation and inhibit apoptosis, whereas transfection with miR-32-3p inhibitor had the opposite effect. Conclusion: miR-32-3p demonstrates significant diagnostic potential for OPF patients. It is likely that miR-32-3p probably is a new diagnosis biomarker for OPF, offering promising therapeutic avenues through targeted interventions. [ABSTRACT FROM AUTHOR]

Summary: The novel metaPGS, integrating multiple fracture–related genetic traits, surpasses traditional polygenic scores in predicting fracture risk. Demonstrating a robust association with incident fractures, this metaPGS offers significant potential for enhancing clinical fracture risk assessment and tailoring prevention strategies. Introduction: Current polygenic scores (PGS) have limited predictive power for fracture risk. To improve genetic prediction, we developed and evaluated a novel metaPGS combining genetic information from multiple fracture–related traits. Methods: We derived individual PGS from genome-wide association studies of 16 fracture-related traits and employed an elastic-net logistic regression model to examine the association between the 16 PGSs and fractures. An optimal metaPGS was constructed by combining 11 significant individual PGSs selected by the elastic regularized regression model. We evaluated the predictive power of the metaPGS alone and in combination with clinical risk factors recommended by guidelines. The discrimination ability of metaPGS was assessed using the concordance index. Reclassification was assessed using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Results: The metaPGS had a significant association with incident fractures (HR 1.21, 95% CI 1.18–1.25 per standard deviation of metaPGS), which was stronger than previously developed bone mineral density (BMD)-related individual PGSs. Models with PGS_FNBMD, PGS_TBBMD, and metaPGS had slightly higher but statistically non-significant c-index than the base model (0.640, 0.644, 0.644 vs. 0.638). However, the reclassification analysis showed that compared to the base model, the model with metaPGS improves the reclassification of fracture. Conclusions: The metaPGS is a promising approach for stratifying fracture risk in the European population, improving fracture risk prediction by combining genetic information from multiple fracture–related traits. [ABSTRACT FROM AUTHOR]

Summary: Osteoporosis-pseudoglioma syndrome (OPPG) and LRP5 high bone mass (LRP5-HBM) are two rare bone diseases with opposite clinical symptoms caused by loss-of-function and gain-of-function mutations in LRP5. Bisphosphonates are an effective treatment for OPPG patients. LRP5-HBM has a benign course, and age-related bone loss is found in one LRP5-HBM patient. Purpose: Low-density lipoprotein receptor-related protein 5 (LRP5) is involved in the canonical Wnt signaling pathway. The gain-of-function mutation leads to high bone mass (LRP5-HBM), while the loss-of-function mutation leads to osteoporosis-pseudoglioma syndrome (OPPG). In this study, the clinical manifestations, disease-causing mutations, treatment, and follow-up were summarized to improve the understanding of these two diseases. Methods: Two OPPG patients and four LRP5-HBM patients were included in this study. The clinical characteristics, biochemical and radiological examinations, pathogenic mutations, and structural analysis were summarized. Furthermore, several patients were followed up to observe the treatment effect and disease progress. Results: Congenital blindness, persistent bone pain, low bone mineral density (BMD), and multiple brittle fractures were the main clinical manifestations of OPPG. Complex heterozygous mutations were detected in two OPPG patients. The c.1455G > T mutation in exon 7 was first reported. During the follow-up, BMD of two patients was significantly improved after bisphosphonate treatment. On the contrary, typical clinical features of LRP5-HBM included extremely high BMD without fractures, torus palatinus and normal vision. X-ray showed diffuse osteosclerosis. Two heterozygous missense mutations were detected in four patients. In addition, age-related bone loss was found in one LRP5-HBM patient after 12-year of follow-up. Conclusion: This study deepened the understanding of the clinical characteristics, treatment, and follow-up of OPPG and LRP5-HBM; expanded the pathogenic gene spectrum of OPPG; and confirmed that bisphosphonates were effective for OPPG. Additionally, it was found that Ala242Thr mutation could not protect LRP5-HBM patients from age-related bone loss. This phenomenon deserves further study. [ABSTRACT FROM AUTHOR]

Summary: This large-scale prospective study showed that a significant association between longer duration of daily outdoor walking and reduced osteoporosis risk was found among older adults, particularly among those with a low genetic predisposition to osteoporosis, which highlighted the importance of outdoor walking as a simple, cost-effective adjunct for preventing osteoporosis. Purpose: The available cross-sectional data and small-scale studies indicate that outdoor walking benefits bone metabolism. Nevertheless, there is a scarcity of comprehensive prospective research investigating the enduring correlation between outdoor walking and osteoporosis. This study aims to conduct a prospective analysis of the correlation between outdoor walking and osteoporosis while also examining potential variations influenced by genetic susceptibility to osteoporosis. Methods: 24,700 older adults without osteoporosis at baseline were enrolled. These individuals were followed up until December 31, 2021, during which data on outdoor walking was gathered. The genetic risk score for osteoporosis was comprised of 14 single-nucleotide polymorphisms. Results: 4,586 cases of osteoporosis were identified throughout a median follow-up period of 37.3 months. Those who walked outside for > 30 but ≤ 60 min per day had a hazard ratio (HR) of 0.83 (95% confidence interval (CI): 0.72–0.95) for incident osteoporosis, whereas those who walked outside for > 60 min per day had an HR of 0.60 (95% CI: 0.39–0.92). We found that osteoporosis risk exhibited a declining trend in individuals with low genetic risk. Individuals walking outside for > 60 min per day tended to have the lowest overall osteoporosis risk among those with high genetic risk. Conclusions: A significant negative correlation exists between an extended period of daily outdoor walking and osteoporosis incidence risk. This correlation is particularly pronounced among individuals with low genetic risk. The results above underscore the significance of outdoor walking as a simple and economical adjunct to public health programs to prevent osteoporosis. [ABSTRACT FROM AUTHOR]

Objectives: Genetic factors are a major cause of osteoporosis. The present study evaluated the association of the apolipoprotein E (ApoE) genotype with bone mineral density (BMD) and its response to menopausal hormone therapy (MHT) in postmenopausal Korean women. Methods: This retrospective cohort study included 172 postmenopausal women with no endocrine diseases, medications, or lifestyles that would affect bone metabolism and who were continuously treated with MHT for at least 2 years. BMDs were measured at baseline and periodically. Results: Linear regression analysis demonstrated similar baseline BMDs at the lumbar spine, but significantly lower at the femur neck and total hip in the ApoE e4 carrier than in the noncarrier group, after controlling for age, body mass index, and history of MHT usage. Overall, the Wilcoxon signed rank test demonstrated that MHT increased the BMD percentage change at all three regions, and the Generalized Estimating Equation (GEE) demonstrated significant time trends at the lumbar spine and femur neck. ApoE e4 noncarriers exhibited a significant time trend in BMD changes at the femur neck, whereas e4 carriers exhibited a time trend at the lumbar spine. However, BMD changes at each time point were comparable at all regions between the groups. Notably, GEE adjusted for baseline characteristics and BMD revealed a significant interaction effect of time and ApoE e4 allele in BMD changes at the femur neck. Conclusions: Postmenopausal Korean women carrying the ApoE e4 allele demonstrated a lower hip BMD compared with e4 noncarriers. Furthermore, the e4 allele may modulate hip BMD responses to MHT. [ABSTRACT FROM AUTHOR]

Summary: Bone mineral density (BMD) is an essential predictor of osteoporosis and fracture. We conducted a genome-wide trajectory analysis of BMD and analyzed the BMD change. Purpose: This study aimed to identify the genetic architecture and potential biomarkers of BMD. Methods: Our analysis included 141,261 white participants from the UK Biobank with heel BMD phenotype data. We used a genome-wide trajectory analysis tool, TrajGWAS, to conduct a genome-wide association study (GWAS) of BMD. Then, we validated our findings in previously reported BMD genetic associations and performed replication analysis in the Asian participants. Finally, gene-set enrichment analysis (GSEA) of the identified candidate genes was conducted using the FUMA platform. Results: A total of 52 genes associated with BMD trajectory mean were identified, of which the top three significant genes were WNT16 (P = 1.31 × 10−126), FAM3C (P = 4.18 × 10−108), and CPED1 (P = 8.48 × 10−106). In addition, 114 genes associated with BMD within-subject variability were also identified, such as AC092079.1 (P = 2.72 × 10−13) and RGS7 (P = 4.72 × 10−10). The associations for these candidate genes were confirmed in the previous GWASs and replicated successfully in the Asian participants. GSEA results of BMD change identified multiple GO terms related to skeletal development, such as SKELETAL SYSTEM DEVELOPMENT (Padjusted = 2.45 × 10−3) and REGULATION OF OSSIFICATION (Padjusted = 2.45 × 10−3). KEGG enrichment analysis showed that these genes were mainly enriched in WNT SIGNALING PATHWAY. Conclusions: Our findings indicated that the CPED1-WNT16-FAM3C locus plays a significant role in BMD mean trajectories and identified several novel candidate genes contributing to BMD within-subject variability, facilitating the understanding of the genetic architecture of BMD. [ABSTRACT FROM AUTHOR]

Summary: It remains unclear whether the relationship between type 2 diabetes mellitus (T2DM) and bone mineral density (BMD) reflects causality in East Asian populations. Herein, a Mendelian randomization study conducted in East Asian population enhances the current clinical cognition that T2DM is not associated with reduction in BMD. Purpose: A Mendelian randomization (MR) approach was utilized to investigate the relationship between type 2 diabetes mellitus (T2DM) and bone mineral density (BMD) in East Asian populations. Methods: Genome-wide association study summary data from BioBank Japan were used to identify genetic variants strongly related to T2DM risk (36,614 cases and 155,150 controls) and osteoporosis (7788 cases and 204,665 controls). Heel BMD GWAS data of 1260 East Asian people from ieu open gwas project was considered as a second outcome. Inverse variance-weighted (IVW) analysis was mainly applied; MR-Egger and the weighted median were also used to obtain robust estimates. A series of sensitivity analyses including Cochran's Q test, MR-Egger regression, and leave-one-out analysis were used to detect pleiotropy or heterogeneity. Results: In the main analysis, IVW estimates indicated that T2DM significantly associated with the risk of osteoporosis (odds ratio = 0.92, 95% CI: 0.86–0.99, p = 0.016) and with higher BMD (OR: 1.25, 95% CI: 1.06–1.46, p = 6.49 × 10−3). Results of comprehensive sensitivity analysis were consistent with the main causality estimate. Horizontal pleiotropy and heterogeneity were absent in our MR study. Conclusions: T2DM is not associated with reduction in BMD in terms of genetic polymorphism in East Asian populations. [ABSTRACT FROM AUTHOR]

Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder characterized by severe osteoporosis and eye abnormalities that lead to vision loss. In this study, clinical findings and genetic study of two siblings with OPPG are presented. Whole exome sequencing of DNA enriched for exonic regions was performed with SureSelect 38Mbp all exon kit v. 7.0. The two siblings presented with different clinical manifestations of OPPG. The younger female sibling had blindness and severe osteoporosis with multiple fractures, while her older brother was also blind but with less severe osteoporosis and no fractures. On analysis, a novel homozygous nonsense mutation (c.351G>A) in exon 2 of LRP5 (NM_002335) was found, predicted to change a tryptophan at 117 to a stop codon (p. Trp117Ter). Thus, a variable phenotype was associated with an identical variant in these two siblings. The novel mutation reported herein expands the spectrum of the underlying genetic pathology of OPPG. [ABSTRACT FROM AUTHOR]

Background: miRNAs are closely related to bone metabolism. Studies have shown that Erxian decoction can improve bone metabolism, possibly achieving this regulatory effect through miRNA targets. Netinfer was used to predict the miRNA targets of Erxian decoction for the treatment of postmenopausal osteoporosis, and the results were validated by clinical trials. Methods: In this study, we identified possible targets of Erxian decoction in osteoporosis by means of network pharmacological analysis and bioinformatic prediction. Fifteen cases of postmenopausal osteoporosis with kidney Yin and Yang deficiency (In traditional Chinese medicine, kidney Yin nourishes and moistens the tissues of the internal organs of the body, while kidney Yang promotes and warms the tissues of the internal organs of the body.) were treated with Erxian decoction for four weeks, and serum bone metabolism indices (P1NP, osteocalcin, and ß-CTX) and miRNA-335-5p expression were measured before and after treatment. Results: The constructed miRNA postmenopausal osteoporosis related gene network of the effective compound of the Erxian decoction has 296 points and 981 edges. The 39 postmenopausal osteoporosis related genes regulated by miRNA-335-5p were enriched in ossification, while the signaling pathways were enriched in rheumatoid arthritis, the Toll signaling pathway, the HIF-1 signaling pathway, and the MAPK signaling pathway. After taking Erxian decoction, the expression of the serum bone formation index (P1NP, osteocalcin) and miRNA-335-5p gene expression levels increased significantly. The alterations in P1NP and osteocalcin were correlated with the changes in miRNA-335-5p. Conclusion: Circulating miRNA-335-5p may serve as an important target of Erxian decoction in the treatment of postmenopausal women. The effect of Erxian decoction on bone formation is significant, but the underlying mechanism requires further investigation. [ABSTRACT FROM AUTHOR]

Objectives: To assess LRP5-/6 gene polymorphisms and its association with risk of abnormal bone mass (ABM) in postmenopausal women. Methods: The study recruited 166 patients with ABM (case group) and 106 patients with normal bone mass (control group) based on bone mineral density (BMD) results. Multi-factor dimensionality reduction (MDR) was used to analyze the interaction between the Low-density lipoprotein receptor-related protein 5 (LRP5) gene (rs41494349, rs2306862) and the Low-density lipoprotein receptor-related protein 6 (LRP6) gene (rs10743980, rs2302685) and the subjects' clinical characteristics of age and menopausal years. Results: (1) Logistic regression analysis showed that the subjects with the CT or TT genotype at rs2306862 had a higher risk of ABM than those with the CC genotype (OR = 2.353, 95%CI = 1.039–6.186; OR = 2.434, 95%CI = 1.071, 5.531; P < 0.05). The subjects with the TC genotype at rs2302685 had a higher risk of ABM than those with the TT genotype (OR = 2.951, 95%CI = 1.030–8.457, P < 0.05). (2) When taking the three Single-nucleotide polymorphisms (SNPs) together, the accuracy was the highest with the cross-validation consistency of 10/10 (OR = 1.504, 95%CI:1.092–2.073, P < 0.05), indicating that the LRP5 rs41494349 and LRP6 rs10743980, rs2302685 were interactively associated with the risk of ABM. (3) Linkage disequilibrium (LD) results revealed that the LRP5 (rs41494349,rs2306862) were in strong LD (D′ > 0.9, r2 > 0.3). AC and AT haplotypes were significantly more frequently distributed in the ABM group than in the control group, indicating that subjects carrying the AC and AT haplotypes were associated with an increased risk of ABM (P < 0.01). (4) MDR showed that rs41494349 & rs2302685 & rs10743980 & age were the best model for ABM prediction. The risk of ABM in "high-risk combination" was 1.00 times that of "low-risk combination"(OR = 1.005, 95%CI: 1.002–1.008, P < 0.05). (5) MDR showed that there was no significant association between any of the SNPs and menopausal years and ABM susceptibility. Conclusion: These findings indicate that LRP5-rs2306862 and LRP6-rs2302685 polymorphisms and gene–gene and gene–age interactions may increase the risk of ABM in postmenopausal women. There was no significant association between any of the SNPs and menopausal years and ABM susceptibility. [ABSTRACT FROM AUTHOR]

Osteoporosis (OP) is commonly encountered, which is a kind of systemic injury of bone mass and microstructure, leading to brittle fractures. With the aging of the population, this disease will pose a more serious impact on medical, social, and economic aspects, especially postmenopausal osteoporosis (PMOP). This study is aimed at figuring out potential therapeutic targets and new biomarkers in OP via bioinformatics tools. After differentially expressed gene (DEG) analysis, we successfully identified 97 upregulated and 172 downregulated DEGs. They are mainly concentrated in actin binding, regulation of cytokine production, muscle cell promotion, chemokine signaling pathway, and cytokine-cytokine receiver interaction. According to the diagram of protein-protein interaction (PPI), we obtained 10 hub genes: CCL5, CXCL10, EGFR, HMOX1, IL12B, CCL7, TBX21, XCL1, PGR, and ITGA1. Expression analysis showed that Egfr, Hmox1, and Pgr were significantly upregulated in estrogen-treated osteoporotic patients, while Ccl5, Cxcl10, Il12b, Ccl7, Tbx21, Xcl1, and Itga1 were significantly downregulated. In addition, the analysis results of Pearson's correlation revealed that CCL7 has a strong positive association with IL12b, TBX21, and CCL5 and so was CCL5 with IL12b. Conversely, EGFR has a strong negative association with XCL1 and CXCL10. In conclusion, this study screened 10 hub genes related to OP based on the GEO database, laying a biological foundation for further research on new biomarkers and potential therapeutic targets in OP. [ABSTRACT FROM AUTHOR]

Objective: Osteoporosis is a progressive systemic skeletal disorder. Multiple profiling studies have contributed to characterizing biomarkers and therapeutic targets for osteoporosis. However, due to the limitation of the platform of miRNA sequencing, only a part of miRNA can be sequenced based on one platform. Materials and methods: In this study, we performed miRNA sequencing in osteoporosis bone samples based on a novel platform Illumina Hiseq 2500. Bioinformatics analysis was performed to construct osteoporosis-related competing endogenous RNA (ceRNA) networks. Gene interference and osteogenic induction were used to examine the effect of identified ceRNA networks on osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (HBMSCs). Results: miR-1303 was lowly expressed, while cochlin (COCH) and KCNMA1-AS1 were highly expressed in the osteoporosis subjects. COCH knockdown improved the osteogenic differentiation of HBMSCs. Meanwhile, COCH inhibition compensated for the suppression of osteogenic differentiation of HBMSCs by miR-1303 knockdown. Further, KCNMA1-AS1 knockdown promoted osteogenic differentiation of HBMSCs through downregulating COCH by sponging miR-1303. Conclusions: Our findings suggest that the KCNMA1-AS1/miR-1303/COCH axis is a promising biomarker and therapeutic target for osteoporosis. [ABSTRACT FROM AUTHOR]

Summary: We present a family with a rare mutation of the LRP6 gene and for the first time provide evidence for its association with low bone mineral density. Introduction: The Wnt pathway plays a critical role in bone homeostasis. Pathogenic variants of the Wnt co-receptor LRP6 have been associated with abnormal skeletal phenotypes or increased risk of cardiovascular events. Patient and methods: Here we report an index premenopausal patient and her family carrying a rare missense LRP6 pathogenic variant (rs141212743; 0.0002 frequency among Europeans). This variant has been previously associated with metabolic syndrome and atherosclerosis, in the presence of normal bone mineral density. However, the LRP6 variant was associated with low bone mineral density in this family, without evidence for association with serum lipid levels or cardiovascular events. Conclusion: Thus, this novel association shows that LRP6 pathogenic variants may be involved in some cases of early-onset osteoporosis, but the predominant effect, either skeletal or cardiovascular, may vary depending on the genetic background or other acquired factors. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis (OP) patients complicated with type II diabetes mellitus (T2DM) has a higher fracture risk than the non-diabetic patients, and mesenchymal stem cells (MSCs) from T2DM patients also show a weaker osteogenic potent. The present study aimed to provide a gene expression profile in MSCs from diabetic OP and investigated the potential mechanism. Methods: The bone-derived MSC (BMSC) was isolated from OP patients complicated with or without T2DM (CON-BMSC, T2DM-BMSC). Osteogenic differentiation was evaluated by qPCR analysis of the expression levels of osteogenic markers, ALP activity and mineralization level. The differentially expressed genes (DEGs) in T2DM-BMSC was identified by RNA-sequence, and the biological roles of DEGs was annotated by bioinformatics analyses. The role of silencing the transcription factor (TF), Forkhead box Q1 (FOXQ1), on the osteogenic differentiation of BMSC was also investigated. Results: T2DM-BMSC showed a significantly reduced osteogenic potent compare to the CON-BMSC. A total of 448 DEGs was screened in T2DM-BMSC, and bioinformatics analyses showed that many TFs and the target genes were enriched in various OP- and diabetes-related biological processes and pathways. FOXQ1 had the highest verified fold change (abs) among the top 8 TFs, and silence of FOXQ1 inhibited the osteogenic differentiation of CON-BMSC. Conclusions: Our study provided a comprehensive gene expression profile of BMSC in diabetic OP, and found that downregulated FOXQ1 was responsible for the reduced osteogenic potent of T2DM-BSMC. This is of great importance for the special mechanism researches and the treatment of diabetic OP. [ABSTRACT FROM AUTHOR]

Osteoporosis (OP) predominantly affects elderly individuals. Stem cells show potential for treating OP. However, animal models with normal immune function can eliminate implanted human cells. This study utilized naturally aging NOD/SCID mice, which exhibit immunodeficiency, to create a human osteoporosis model. This approach helps to minimize the premature immune clearance of transplanted allogeneic or xenogeneic cells in preclinical studies, allowing for a more accurate replication of the clinical pharmacological and pharmacokinetic processes involved in stem cell interventions for osteoporosis. NOD/SCID mice were fed until 12, 32, and 43 weeks of age, respectively, and then euthanized. We harvested lumbar vertebra for Micro-Computed Tomography (Micro-CT) scanning and pathological examination. Additionally, we performed biomechanical testing of lumbar vertebra to assess the severity of osteoporosis. We utilized real-time RT-PCR to assess gene expression changes associated with bone metabolism, aging, inflammation, oxidative stress, and the Tgf-β1/Smad3 signaling pathway. In addition, the protein expression levels of P16, Tgf-β1 and Smad3 were detected using Western Blotting (WB). In comparison to 12-week-old mice, the 32-week-old and 43-week-old mice displayed significantly sparser and fractured trabeculae in their lumbar vertebra, lower bone mineral density (BMD), and changes in bone microstructural parameters (∗∗P < 0.01, ∗∗∗P < 0.001). Additionally, compared to 12-week-old mice, the 32-week-old and 43-week-old mice exhibited decreased expression of osteogenic genes (Alp, Opg, Sp7, Col1a1), increased expression of osteoclastic gene (Rankl), the number of TRAP-positive osteoclasts significantly increased in 32-week-old and 43-week-old mice compared to 12-week-old mice. The expression of genes related to aging and inflammatory (P16, Il-1β, Tnf-α) increases with advancing age (∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001). The expression of oxidative stress-related genes (Sod1, Sod2, Foxo3, Nrf2), as well as Tgf-β1 and Smad3 decreased with age (∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001). As age increases, the levels of P16 protein increase, Tgf-β1 and Smad3 proteins decrease. Our study successfully replicated osteoporosis models in NOD/SCID mice at both 32 and 43 weeks, with the latter exhibiting more severe osteoporosis. This condition seems to be driven by factors such as aging, inflammation, oxidative stress, and the Tgf-β1/Smad3 signaling pathway., Competing Interests: Declaration of competing interest Zhaoxia Ma, Lihua Qiu, Jinyan Li, Zhen Wu, Shu Liang, Yunhui Zhao, Jinmei Yang, Min Hu and Yanjiao Li declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Primary osteoporosis, manifesting as decreased bone mass and increased bone fragility, is a "silent disease" that is often ignored until a bone breaks. Accordingly, it is urgent to develop reliable biomarkers and novel therapeutic strategies for osteoporosis treatment. Here, we identified REGγ as a potential biomarker of osteoporotic populations through proteomics analysis. Next, we demonstrated that REGγ deficiency increased osteoclast activity and triggered bone mass loss in REGγ knockout (KO) and bone marrow-derive macrophage (BMM)-conditional REGγ KO mice. However, the osteoclast activity decreased in BMM-conditional REGγ overexpression mice. Mechanistically, we defined that REGγ-20S proteasome directly degraded TRAF6 to inhibit bone absorption in a ubiquitin-independent pathway. More importantly, BMM-conditional Traf6 KO with REGγ KO mice could "rescue" the osteoporosis phenotypes. Based on NIP30 (a REGγ "inhibitor") dephosphorylation by CKII inhibition activated the ubiquitin-independent degradation of TRAF6, we selected TTP22, an inhibitor of CKII, and defined that TTP22 could alleviate osteoporosis in vitro and in vivo. Overall, our study reveals a unique function of NIP30/REGγ/TRAF6 axis in osteoporosis and provides a potential therapeutic drug TTP22 for osteoporosis., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Epithelial stromal interaction 1 (EPSTI1) plays an important role in M1 macrophages, which induce osteoclastogenesis. One recent genome-wide association study (GWAS) involving 426,824 individuals has shown that EPSTI1 is strongly associated with osteoporosis (P < 5E-8). Therefore, we speculate that EPSTI1 participates in the modulation of osteoporosis through osteoclastogenesis. The roles of EPSTI1 in osteoclastogenesis and bone resorption remain unclear., Methods: Femur specimens were collected from osteoporotic patients and control patients. Immunofluorescence staining was used to detect the expression of EPSTI1 and signaling pathways. The osteoclastic potential of RAW264.7 cells with Sh-EPSTI1 lentivirus infection was tested using tartrate-resistant acid phosphatase (TRAP) staining, western blotting, and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Western blotting was also used to examine signaling pathways., Results: In this study, EPSTI1 was found to be significantly increased in tartrate-resistant acid phosphatase positive (ACP5 + ) osteoclasts of bone sections from osteoporotic patients. Next, we identified EPSTI1 as a positive regulator of osteoclastogenesis and osteoclast differentiation capability. Diminished EPSTI1 expression resulted in reduced osteoclastic resorption. Mechanistically, EPSTI1-driven osteoclastogenesis was regulated by NF-κB pathway, which was mediated by the phosphorylation of protein kinase R (p-PKR). Furthermore, EPSTI1 participating in the modulation of osteoporosis via PKR/NF-κB pathway was also verified in the bone samples of osteoporotic patients., Conclusions: Collectively, our findings suggest that EPSTI1 may regulate osteoclast differentiation and bone resorption through PKR/NF-κB pathway and in vivo experiments are needed to further verify EPSTI1 as the therapy target for osteoporosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Osteoporosis (OP) is a metabolic bone disease characterized by progressive decline of bone mass and bone quality, leading to bone fragility and an increased risk of fracture. The osteogenic differentiation of bone mesenchymal stem cells (BMSCs) is crucial to maintain the balance of osteoblast and osteoclast. Bioinformatics prediction indicates that ZFP36 ring finger protein (ZFP36), an RNA-binding protein, is a potential target of OP. Herein, we sought to probe the regulatory role and mechanisms of ZFP36 in the progression of OP. Overexpression of ZFP36 enhanced osteoblast viability, differentiation and mineralization of human BMSCs (hBMSCs). RNA immunoprecipitation qPCR (RIP-qPCR) assays demonstrated that ZFP36 could inhibit the translation of JUN, which was also verified with dual luciferase reporter gene assay. Furthermore, administration with T-5224, a transcription factor c-Fos/activator protein (AP)-1 inhibitor, which specifically inhibits the DNA binding activity of c-Fos/JUN, abolished the effect of ZFP36 knockdown on the behaviors of hBMSCs, suggesting that ZFP36 might promotes osteogenic differentiation through regulating JUN. These findings provide insights into the progression and a potential therapeutic target of OP., Competing Interests: Declarations Competing interests The authors declare no competing interests. Conflict of interest The authors declare that there is no conflict interest., (© 2024. The Author(s).)

Background: The role of vitamin C as an antioxidant in guarding against osteoporosis in adults is still debated. This research employs both a cross-sectional study and a two-sample bidirectional Mendelian randomization (MR) analysis to explore how serum vitamin C levels correlate with the incidence of osteoporosis among adults., Methods: In this study, we utilized data from the National Health and Nutrition Examination Survey (NHANES) database for the years 2003-2006, and 2017-2018 to conduct both a cross-sectional analysis and MR to investigate the relationship between serum vitamin C levels and the risk of osteoporosis in adults. We adjusted our analyses for essential demographic and lifestyle variables, and applied logistic regression techniques. Genetic determinants of vitamin C levels were analyzed through MR, using methods like inverse-variance weighted (IVW) and MR-Egger to assess causality. Statistical computations were carried out in R, incorporating visual tools such as restricted cubic spline curves (RCS) and forest plots to clarify the dose-response dynamics and variations across different subgroups. This study was approved by the NCHS Ethics Review Board, and informed consent was obtained from all participants., Results: In our investigation, we analyzed data from 3,940 participants, among whom 291 were diagnosed with osteoporosis. The logistic regression analysis of serum vitamin C quartiles did not indicate a significant trend. The most adjusted model showed a slight, albeit inconsistent, protective effect in the highest quartile (OR = 0.68, 95% CI: 0.47-0.99, P = 0.22). Mendelian randomization, employing methods such as IVW, reinforced the absence of a significant causal relationship between serum vitamin C levels and osteoporosis risk (IVW OR = 1.000, 95% CI: 0.999-1.001, P = 0.601).Subgroup analyses, visualized through forest plots and restricted cubic spline (RCS) curves, supported the primary findings, showing no significant effects or interactions between vitamin C levels and osteoporosis risk across different demographic and lifestyle subgroups. The RCS analysis particularly highlighted a lack of significant non-linear relationships between serum vitamin C concentration and the odds of osteoporosis (P for nonlinear = 0.840)., Conclusions: The cross-sectional study revealed that higher serum vitamin C levels do not consistently correlate with a reduced risk of osteoporosis. Meanwhile, the Mendelian randomization analysis confirmed that there is no genetic evidence to suggest a causal relationship between vitamin C levels and osteoporosis risk. Recent research highlights the polygenic nature of osteoporosis, with genetic predispositions playing a significant role in disease risk. The relationship between serum vitamin C and osteoporosis requires further research. This suggests the need for further investigation into the connection between vitamin C and bone health., (© 2024. The Author(s).)

Employing a two-sample Mendelian randomization (MR) analysis, we aimed to investigate the potential causal effect of Parkinson disease (PD) on osteoporosis. We conducted an in-depth MR analysis by leveraging extensive genome-wide association study datasets from the International Parkinson Disease Genomics Consortium and the Genetic Factors for Osteoporosis Consortium. We meticulously selected instrumental variables based on strict criteria, including significance thresholds, linkage disequilibrium, and the exclusion of confounding single-nucleotide polymorphisms. Our investigation utilized diverse MR methods, including inverse variance weighted, MR Egger regression, weighted median, and MR-PRESSO, to robustly evaluate the causal relationship. Our comprehensive analysis revealed noteworthy associations between PD and distinct measures of bone mineral density (BMD) (forearm BMD, femoral neck BMD, lumbar spine BMD). Specifically, the inverse variance weighted method underscored potential significant relationships between PD and forearm BMD (P = .037; odds ratio [OR], 1.04; 95% confidence interval [CI], 1.00-1.09), femoral neck BMD (P = .034; OR, 1.02; 95% CI, 1.00-1.05), and lumbar spine BMD (P = .043; OR, 1.03; 95% CI, 1.00-1.06). The consistency of results across various methods and sensitivity analyses indicated both robustness and minimal pleiotropy concerns. Through a two-sample MR approach, this study establishes a plausible causal relationship between PD and decreased BMD. The outcomes underscore the urgency of targeted interventions to mitigate bone loss and manage osteoporosis in individuals with PD., Competing Interests: The authors have no conflicts of interests to disclose, (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Osteoporosis manifests through adipocyte accrual and osteoblast diminution within bone marrow. However, the precise mechanisms driving the shift from osteogenesis to adipogenesis in bone marrow mesenchymal stem cells (BMSCs) remain largely undefined. In this study, we harnessed the power of bioinformatic tools to analyze gene expression patterns of BMSCs during adipogenic differentiation and osteoporosis using the data from Gene Expression Omnibus (GEO) repositories (GSE113253 and GSE35956), complemented by in vitro and in vivo experiments to validate the findings. Five distinct expression profiles of differentially expressed genes across the adipogenic timeline were identified. The initial phase is marked by ribosome biogenesis and rRNA processing, which is followed by the metabolism of organic acids and processing of inorganic ions. In contrast, the terminal phase is characterized by lipid transport, accumulation, and metabolism, alongside inorganic cation metabolism, thereby underscoring unique transcriptional signatures during the early and late stages of adipogenic differentiation. In BMSCs derived from osteoporotic samples, there is a notable decline in cellular proliferation and a diminished osteogenic capacity. Critically, the genes common to both adipogenesis and osteoporosis in BMSCs are predominantly involved in the negative regulation of Wnt signaling and cellular proliferation. Key genes including SOCS1, MYC, CEBPB, FYN, AXIN2, and RXRA are identified and show downregulation in BMSCs from aged mice. Subsequent in vitro experiments have validated the regulatory influence of RXRA on both adipogenic and osteogenic differentiations of BMSCs, highlighting its crucial role as a central modulator in bone formation and the pathophysiology of osteoporosis., (© 2024 John Wiley & Sons, Ltd.)

Osteoporosis is a common degenerative skeletal disease among older people, especially postmenopausal women. Bone marrow mesenchymal stem cells (BMSCs), the progenitors of osteoblasts, are essential to the pathophysiology of osteoporosis. Herein, targeting miRNAs with differential expression in dysfunctional BMSCs was accomplished by bioinformatics analysis based on public databases. Target mRNAs were predicted and applied for signaling pathway and function enrichment annotations. In vitro and in vivo effects of selected miRNA on BMSC proliferation and osteogenesis were investigated, the putative binding between selected miRNA and predicted target mRNA was verified, and the co-effects of the miRNA/mRNA axis on BMSCs were determined. miRNA 665 (miR-665) was down-regulated in osteoporotic BMSCs compared with normal BMSCs and elevated in BMSCs experiencing osteogenic differentiation. In BMSCs, miR-665 overexpression promoted cell proliferation and osteogenic differentiation. miR-665 targeted the Wnt signaling inhibitor sclerostin (SOST) and inhibited SOST mRNA and protein expression. SOST overexpression inhibited BMSC cell proliferation and osteogenic differentiation. When co-transduced to BMSCs, SOST knockdown significantly reversed the effects of miR-665 on BMSCs. In ovariectomy (OVX)-induced osteoporosis model mice, OVX remarkably decreased bone mass, whereas miR-665 overexpression partially improved OVX-induced bone mass loss. miR-665 was down-regulated in osteoporotic BMSCs and up-regulated in osteogenically differentiated BMSCs. In conclusion, the miR-665/SOST axis modulates BMSC proliferation, osteogenic differentiation, and OVX-induced osteoporosis in mice, possibly through Wnt signaling., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: Osteoporosis (OP) is a common cause of morbidity and mortality in older individuals. The importance of Wnt3a in osteogenic activity and bone tissue homeostasis is well known. Here, we explored the possible molecular mechanism by which Wnt3a mediates the LRP6/mTORC1/β-catenin axis to regulate osteoblast differentiation in OP., Methods: OP-related key genes were identified through a bioinformatics analysis. A ROS17/2.8 cell differentiation system for rat osteogenic progenitors and a rat model of senile OP were constructed for in vitro and in vivo mechanism verification., Results: Bioinformatics analysis revealed that LRP6 was poorly expressed in OP and may play a key role in the occurrence of OP by affecting osteoblast differentiation. LRP6 knockdown inhibited osteoblast differentiation in an in vitro model. In addition, Wnt3a promoted osteoblast differentiation by inducing LRP6 phosphorylation. Moreover, LRP6 promoted mTORC1 expression, which indirectly promoted β-catenin expression, thus promoting osteoblast differentiation. Finally, an in vivo assay revealed that LRP6 inhibition improved OP., Conclusion: Our study provides evidence that Wnt3a induces phosphorylation of LRP6 to activate the mTORC1/β-catenin axis, thus promoting osteoblast differentiation and ultimately improving OP in aged rats., (Copyright © 2024. Published by Elsevier Inc.)

Osteoporosis is a skeletal disorder characterized by abnormal bone microarchitecture and low bone mineral density (BMD), responsible for an increased risk of fractures and skeletal fragility. It is a common pathology of the aging population. However, when osteoporosis occurs in children or young adults, it strongly suggests an underlying genetic etiology. Over the past two decades, several genes have been identified as responsible for this particular kind of considered monogenic early-onset osteoporosis (EOOP) or juvenile osteoporosis, the main ones being COL1A1, COL1A2, LRP5, LRP6, WNT1, and more recently PLS3. In this study, the objective was to characterize a large cohort of patients diagnosed with primary osteoporosis and to establish its diagnosis yield. The study included 577 patients diagnosed with primary osteoporosis and its diagnosis yield was established. To this end, next-generation sequencing (NGS) of a panel of 21 genes known to play a role in bone fragility was carried out. A genetic etiology was explained in about 18% of cases, while the others remain unexplained. The most frequently identified gene associated with EOOP is LRP5, which was responsible for 8.2% of the positive results (47 patients). As unexpected, 17 patients (2.9%) had a variant in PLS3 which encodes plastin 3. Alterations of PLS3 are associated with dominant X-linked osteoporosis, an extremely rare disease. Given the rarity of this disease, we focused on it. It was observed that males were more affected than females, but it is noteworthy that three females with a particularly severe phenotype were identified. Of these three, two had a variant in an additional gene involved in EOP, illustrating the probable existence of digenism. We significantly increase the number of variants potentially associated with EOOP, especially in PLS3. The results of our study demonstrate that molecular analysis in EOOP is beneficial and useful., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Osteoporosis is a severe bone disease with a complex pathogenesis involving various immune processes. With the in-depth understanding of bone immune mechanisms, discovering new therapeutic targets is crucial for the prevention and treatment of osteoporosis. This study aims to explore novel bone immune markers related to osteoporosis based on single-cell and transcriptome data, utilizing bioinformatics and machine learning methods, in order to provide novel strategies for the diagnosis and treatment of the disease., Methods: Single cell and transcriptome data sets were acquired from Gene Expression Omnibus (GEO). The data was then subjected to cell communication analysis, pseudotime analysis, and high dimensional WGCNA (hdWGCNA) analysis to identify key immune cell subpopulations and module genes. Subsequently, ConsensusClusterPlus analysis was performed on the key module genes to identify different diseased subgroups in the osteoporosis (OP) training set samples. The immune characteristics between subgroups were evaluated using Cibersort, EPIC, and MCP counter algorithms. OP's hub genes were screened using 10 machine learning algorithms and 113 algorithm combinations. The relationship between hub genes and immunity and pathways was established by evaluating the immune and pathway scores of the training set samples through the ESTIMATE, MCP-counter, and ssGSEA algorithms. Real-time fluorescence quantitative PCR (RT-qPCR) testing was conducted on serum samples collected from osteoporosis patients and healthy adults., Results: In OP samples, the proportions of bone marrow-derived mesenchymal stem cells (BM-MSCs) and neutrophils increased significantly by 6.73% (from 24.01% to 30.74%) and 6.36% (from 26.82% to 33.18%), respectively. We found 16 intersection genes and four hub genes (DND1, HIRA, SH3GLB2, and F7). RT-qPCR results showed reduced expression levels of DND1, HIRA, and SH3GLB2 in clinical blood samples of OP patients. Moreover, the four hub genes showed positive correlations with neutrophils (0.65-0.90), immature B cells (0.76-0.92), and endothelial cells (0.79-0.87), while showing negative correlations with myeloid-derived suppressor cells (negative 0.54-0.73), T follicular helper cells (negative 0.71-0.86), and natural killer T cells (negative 0.75-0.85)., Conclusion: Neutrophils play a crucial role in the occurrence and development of osteoporosis. The four hub genes potentially inhibit metabolic activities and trigger inflammation by interacting with other immune cells, thereby significantly contributing to the onset and diagnosis of OP., (© 2024 The Author(s). Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.)

Dysregulated bone homeostasis contributes to multiple diseases including osteoporosis (OP). In this study, osteoporotic mice were successfully generated using ovariectomy to investigate the role of nuclear receptor subfamily 3 group C member 1 (NR3C1) in OP. NR3C1, identified as a significantly upregulated gene in OP using bioinformatic tools, was artificially downregulated in osteoporotic mice. NR3C1 expression was significantly elevated in the femoral tissues of osteoporotic patients, and downregulation of NR3C1 alleviated bone loss and restored bone homeostasis in osteoporotic mice, as manifested by increased ALP- and OCN-positive cells and reduced RANKL/OPG ratio. Downregulation of NR3C1 inhibited osteoclastic differentiation of RAW264.7 cells and mouse bone marrow-derived macrophages (BMDM) and promoted osteogenic differentiation of MC3T3-E1 cells. The transcription factor NR3C1 bound to the cystatin-3 (CST3) promoter to repress its transcription in both RAW264.7 and MC3T3-E1 cells. The downregulation of CST3 reversed the protective effect of NR3C1 downregulation against OP. Ubiquitin-specific-processing protease 10 (USP10)-mediated deubiquitination of NR3C1 improved NR3C1 stability. Downregulation of USP10 inhibited osteoclastic differentiation of RAW264.7 cells and BMDM while promoting osteogenic differentiation of MC3T3-E1 cells. Taken together, USP10-mediated deubiquitination of NR3C1 regulates bone homeostasis by controlling CST3 transcription, providing an attractive therapeutic strategy to alleviate OP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: Background: Recent observational studies have suggested that osteoporosis may be a risk factor for sepsis. To mitigate confounding factors and establish the causal relationship between sepsis and osteoporosis, we conducted a two-sample Mendelian randomization analysis using publicly available summary statistics. Methods: Utilizing summary data from FinnGen Biobank, we employed a two-sample Mendelian randomization (MR) analysis to predict the causal relationship between osteoporosis and sepsis. The MR analysis primarily utilized the inverse variance weighted (IVW) method, supplemented by MR-Egger, weighted median, weighted mode, and simple mode analyses, with Bayesian weighted MR (BWMR) analysis employed for result validation. Sensitivity analyses included MR-PRESSO, "leave-one-out" analysis, MR-Egger regression, and Cochran Q test. Results: In the European population, an increase of one standard deviation in osteoporosis was associated with an 11% increased risk of sepsis, with an odds ratio (OR) of 1.11 (95% CI, 1.06-1.16; P = 3.75E-06). BWMR yielded an OR of 1.11 (95% CI, 1.06-1.67; P = 1.21E-05), suggesting osteoporosis as a risk factor for sepsis. Conversely, an increase of one standard deviation in sepsis was associated with a 26% increased risk of osteoporosis, with an OR of 1.26 (95% CI, 1.11-1.16; P = 0.45E-03). BWMR yielded an OR of 1.26 (95% CI, 1.09-1.45; P = 1.45E-03), supporting sepsis as a risk factor for osteoporosis. Conclusion: There is an association between osteoporosis and sepsis, with osteoporosis serving as a risk factor for the development of sepsis, while sepsis may also promote the progression of osteoporosis., Competing Interests: Conflicts of interest: The authors declare no conflicts of interest in this work., (Copyright © 2024 by the Shock Society.)

Osteoporosis is a complex metabolic bone disease that severely undermines the quality of life and overall health of the elderly. While previous studies have established a close relationship between gut microbiome and host bone metabolism, the role of genetic factors has received less scrutiny. This research aims to identify potential taxa associated with various bone mineral density states, incorporating assessments of genetic factors. Fecal microbiome profiles from 605 individuals (334 females and 271 males) aged 55-65 from the Taizhou Imaging Study with osteopenia (n = 270, 170 women) or osteoporosis (n = 94, 85 women) or normal (n = 241, 79 women) were determined using shotgun metagenomic sequencing. The linear discriminant analysis was employed to identify differentially enriched taxa. Utilizing the Kyoto Encyclopedia of Genes and Genomes for annotation, functional pathway analysis was conducted to identify differentially metabolic pathways. Polygenic risk score for osteoporosis was estimated to represent genetic susceptibility to osteoporosis, followed by stratification and interaction analyses. Gut flora diversity did not show significant differences among various bone mineral groups. After multivariable adjustment, certain species, such as Clostridium leptum, Fusicatenibacter saccharivorans and Roseburia hominis, were enriched in osteoporosis patients. Statistically significant interactions between the polygenic risk score and taxa Roseburia faecis, Megasphaera elsdenii were observed (P for interaction = 0.005, 0.018, respectively). Stratified analyses revealed a significantly negative association between Roseburia faecis and bone mineral density in the low-genetic-risk group (β = -0.045, P < 0.05), while Turicimonas muris was positively associated with bone mineral density in the high-genetic-risk group (β = 4.177, P < 0.05) after multivariable adjustments. Functional predictions of the gut microbiome indicated an increase in pathways related to structural proteins in high-genetic-risk patients, while low-genetic-risk patients exhibited enrichment in enzyme-related pathways. This study emphasizes the association between gut microbes and bone mass, offering new insights into the interaction between genetic background and gut microbiome., Competing Interests: Declaration of competing interest The authors have no disclosures or conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Alzheimer's disease and related dementias (ADRD) and osteoporosis (OP) are 2 prevalent diseases of aging with demonstrated epidemiological association, but the underlying molecular mechanisms contributing to this association are unknown., Methods: We used network analysis of bone and brain transcriptomes to discover common molecular mechanisms underlying these 2 diseases. Our study included RNA-sequencing data from the dorsolateral prefrontal cortex tissue of autopsied brains in 629 participants from ROSMAP (Religious Orders Study and the Rush Memory and Aging Project), with a subgroup of 298 meeting criteria for inclusion in 5 ADRD categories, and RNA array data from transiliac bone biopsies in 84 participants from the Oslo study of postmenopausal women. After developing each network within each tissue, we analyzed associations between modules (groups of coexpressed genes) with multiple bone and neurological traits, examined overlap in modules between networks, and performed pathway enrichment analysis to discover conserved mechanisms., Results: We discovered 3 modules in ROSMAP that showed significant associations with ADRD and bone-related traits and 4 modules in Oslo that showed significant associations with multiple bone outcomes. We found significant module overlap between the 2 networks in modules linked to signaling, tissue homeostasis, and development, and Wingless-related integration site (Wnt) signaling was found to be highly enriched in OP and ADRD modules of interest., Conclusions: These results provide translational opportunities in the development of treatments and biomarkers for ADRD and OP., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Genetic mutations have been reported in a number of bone disorders with or without extra-skeletal manifestations. The purpose of the present study was to investigate the genetic cause in a middle-aged woman with osteoporosis, recurrent fractures and extraskeletal manifestations., Methods: A 56-year-old Indian woman presented to the clinic with complaints of difficulty in walking, recurrent fractures, limb bending, progressive skeletal deformities, and poor overall health. At the age of 37, she had experienced severe anemia with diarrhea, significant weight loss, knuckle pigmentation, and a significant loss of scalp hair. She had received multiple blood transfusions and parenteral iron supplementation with normalization of hemoglobin. Subsequently, she had premature menopause at the age of 37. She died at the age of 61 due to liver failure. Exome sequencing followed by Sanger sequencing were undertaken to identify the potential pathogenic mutations., Results: Genetic investigation identified likely pathogenic mutations in the LRP5 and LGR4 genes. Out of the two mutations, the heterozygous mutation (c.1199C>T) in the LRP5 gene resulted in a non-synonymous substitution of alanine with valine at the 400 th position, and the second mutation (c.1403A>C) in the LGR4 gene led to a non-synonymous substitution of tyrosine with serine at the 468 th residue of the protein. The minor allele frequencies of the c.1199C>T (LRP5) substitution in the 1000 genomes and IndiGenomes databases are 0.0003 and 0.001, while the c.1403A>C (LGR4) substitution has not been reported in these databases. Various in silico prediction tools suggested LGR4 mutation to be pathogenic and LRP5 mutation to be likely pathogenic., Conclusion: Heterozygous mutations in the LRP5 and LGR4 genes had additive deteriorative effects on BMD, resulting in recurrent fractures and bone deformities, and extended the effect to extraskeletal sites, contributing to the poor overall health in this patient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Mehta, Sharma, Goswami, Gupta, Singhal, Srivastava, Chattopadhyay and Singh.)

Osteoporosis is a multifactorial bone disease characterised by reduced bone mass and increased fracture risk. Family studies have made significant contribution in unravelling the genetics of osteoporosis. Yet, most of the underlying molecular and biological mechanisms remain unknown prompting the need for further studies. This review outlines the proper phenotyping and advanced genetic techniques in the form of high-throughput DNA sequencing used to identify genetic factors underlying monogenic osteoporosis in a family-based setting. The steps related to variant filtering prioritisation and curation are also described. From an evolutionary perspective, deleterious risk variants with higher penetrance tend to be rare as a result of negative selection. High-throughput sequencing (HTS) can identify rare variants with large effect sizes which are likely to be missed by candidate gene analysis or genome-wide association studies (GWAS) wherein common variants with small to moderate effect sizes are identified. We also describe the importance of replicating implicated genes, and possibly variants, identified following HTS to confirm their causality. Replication of the gene in other families, singletons or independent cohorts confirms that the shortlisted genes and/or variants are indeed causal. Furthermore, novel genes and/or variants implicated in monogenic osteoporosis require a thorough validation by means of in vitro and in vivo assessment. Therefore, analyses of families can continue to elucidate the genetic architecture of osteoporosis, paving the way for improved diagnostic and therapeutic strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Schembri and Formosa.)

For a long time, the decline in lung function has been regarded as a potential factor associated with the risk of osteoporosis (OP). Although several observational studies have investigated the relationship between lung function and OP, their conclusions have been inconsistent. Given that Mendelian randomization (MR) studies can help reduce the interference of confounding factors on outcomes, we adopted this approach to explore the causal relationship between lung function and OP at the genetic level. To investigate the potential causality between lung function (FVC, FEV1, FEV1/FVC, PEF) and OP, we conducted a MR analysis employing three approaches: inverse variance weighted (IVW), MR-Egger, and weighted median. We used Cochran's Q test to detect potential heterogeneity, MR-Egger regression to evaluate directional pleiotropy, and the MR-PRESSO method to evaluate horizontal pleiotropy. In addition, we used MR-PRESSO and MR radial methods to exclude SNPs exhibiting pleiotropic outliers. Upon identification of potential outliers, we removed them and subsequently ran MR analysis again to assess the reliability of our findings. The MR analysis suggested that there was no causal effect of lung function (FVC, PEF, FEV1/FVC, FEV1) on OP, which is consistent with the. results after excluding potential outliers using MR-PRESSO and MR radial. methods. Sensitivity analysis confirmed the reliability and consistency of these. results. The study concluded that there is no causal link between lung function and OP. The association found in observational studies might be attributable to shared risk factors., (© 2024. The Author(s).)

Idiopathic osteoporosis (IOP) is a rare form of early-onset osteoporosis diagnosed in patients with no known metabolic or hormonal cause of bone loss and unknown pathogenesis. Patients with IOP commonly report both childhood fractures and family history of osteoporosis, raising the possibility of genetic etiologies of IOP. Whole-exome sequencing analyses of different IOP cohorts identified multiple variants in melatonin receptor 1A ( MTNR1A ) with a potential pathogenic outcome. A rare MTNR1A variant (rs374152717) was found in members of an Ashkenazi Jewish family with IOP, and an MTNR1A variant (rs28383653) was found in a nonrelated female IOP cohort (4%). Both variants occur at a substantially higher frequency in Ashkenazi Jewish individuals than in the general population. We investigated consequences of the heterozygous (rs374152717) variant [ MTNR1A c.184+1G>T ( MTNR1A c. 184+1G>T )] on bone physiology. A mouse model of the human rs374152717 variant reproduced the low bone mass (BM) phenotype of young-adult patients with IOP. Low BM occurred because of induction of senescence in mutant osteoblasts followed by compromised differentiation and function. In human cells, introduction of rs374152717 led to translation of a nonfunctional protein and subsequent dysregulation of melatonin signaling. These studies provide evidence that MTNR1A mutations entail a genetic etiology of IOP and establish the rs374152717 variant as a loss-of-function allele that impairs bone turnover by inducing senescence in osteoblasts. The higher prevalence of the MTNR1A variants identified in IOP cohorts versus the general population indicates a greater risk of IOP in those carrying these variants, especially Ashkenazi Jewish individuals bearing the rs374152717 variant.

Diabetes osteoporosis (DOP) is a chronic metabolic bone disease. This study aimed to identify potential biomarkers of DOP and explore their underlying mechanisms through bioinformatics methods and experimental verification. Bioinformatics methods were used to identify differentially expressed genes (DEGs) for DOP based on GEO data and the GeneCards database. GO and KEGG enrichment analyses were used to search the key pathways. The STRING website was used to construct a protein-protein interaction (PPI) network and identify key genes. Then, 50 mg/mL glucose was used to interveneosteoblasts (OBs).CCK-8 and Alizarin Red staining were used to investigate the proliferation and differentiation changes in OBs. Flowcytometry was used to investigate apoptosis. The membrane protein chip, WB, and RT-PCR were used to verify the expression of key targets or pathways about DOP. Forty-two common genes were screened between DOP-related targets and DEGs. GO and KEGG enrichment analysis showed that DOP was mainly associated with cytokine-cytokine receptor interactions, and apoptosis. PPI network analysis showed that TNF, IL1A, IL6, IL1B, IL2RA, Fas ligand (FASLG), and Fas cell surface death receptor (FAS) were key up-regulated genes in the occurrence of DOP. The experiment results show that 50 mg/mL glucose significantly inhibited OBs proliferation but presented an increase in apoptosis. Membrane protein chip, WB, and RT-PCR-verified a significantly active in the expression of TNF/FASLG/FAS pathway. High glucose activated the TNF-α/FAS/FASLG pathway and induced the inflammatory microenvironment and apoptosis, then impaired osteogenic differentiation of OBs. These may be an important mechanism for the occurrence and development of DOP., (© 2024 Federation of American Societies for Experimental Biology.)

In the pathophysiology of osteoarthritis and osteoporosis, articular cartilage and bone represent the target tissues, respectively, but muscle is also involved. Since many changes in energy metabolism occur in muscle with aging, the aim of the present work was to investigate the involvement of carnitine palmitoyl transferase 1b (Cpt1b) in the muscle pathophysiology of the two diseases. Healthy subjects (CTR, n = 5), osteoarthritic (OA, n = 10), and osteoporotic (OP, n = 10) patients were enrolled. Gene expression analysis conducted on muscle and myoblasts showed up-regulation of CPT1B in OA patients; this result was confirmed by immunohistochemical and immunofluorescence analyses and enzyme activity assay, which showed increased Cpt1b activity in OA muscle. In addition, CPT1B expression resulted down-regulated in cultured OP myoblasts. Given the potential involvement of Cpt1b in the modulation of oxidative stress, we investigated ROS levels, which were found to be lower in OA myoblasts, and gene expression of nicotinamide adenine dinucleotide phosphate hydrogen oxidase 4 (Nox4), which resulted up-regulated in OA cells. Finally, the immunofluorescence of BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (Bnip3) showed a decreased expression in OP myoblasts, with respect to CTR and OA. Contextually, through an ultrastructural analysis conducted by Transmission Electron Microscopy (TEM), the presence of aberrant mitochondria was observed in OP muscle. This study highlights the potential role of Cpt1b in the regulation of muscle homeostasis in both osteoarthritis and osteoporosis, allowing for the expansion of the current knowledge of what are the molecular biological pathways involved in the regulation of muscle physiology in both diseases.

Background: The relationship between serum uric acid (SUA) and osteoporosis (OP) has yielded conflicting results in observational studies. This Mendelian randomization (MR) study aims to elucidate the causal association between SUA and OP., Methods: A two-sample MR analysis was conducted using summary-level data from genome-wide association studies (GWAS). Two sets of polygenic instruments strongly associated (p < 5 × 10 -8 ) with SUA were extracted from the CKDGen consortium and UK biobank. Polygenic instruments associated with OP (p < 5 × 10 -8 ) were derived from FinnGen biobank and UK biobank. Inverse variance weighting (IVW) was employed as the primary analysis method. Additionally, we utilized MR-Egger, weighted median, the simple mode method, and the weighted mode as complementary analyses. Cochran's Q statistics were used to assess heterogeneity, with MR-Egger intercept testing and MR pleiotropy residual sum and outlier (MR-PRESSO) to examine horizontal pleiotropy. Sensitivity analysis was performed using the leave-one-out method., Results: The IVW analysis conducted across four groups confirms no significant causal relationship between SUA concentration and OP: UKB-UKB (OR: 1.001, 95% CI: 0.999-1.003, p=0.464), CKD-UKB (OR: 1.001, 95% CI: 0.999-1.003, p=0.349), UKB-Fin (OR: 0.934, 95% CI: 0.747-1.168, p=0.549), CKD-Fin (OR: 1.041, 95%CI: 0.934-1.161, p=0.470). Furthermore, additional four MR analyses corroborated these findings. Upon excluding all outliers identified by the MR-PRESSO test, no significant directional pleiotropy was observed, except for some data heterogeneity noted in the UKB-UKB group (Q=50.65, P=0.002). Additionally, a leave-one-out analysis indicated that no single SNP exerted undue influence on the results., Conclusion: This MR analysis provides convincing genetic evidence that there is no causal association between SUA and OP, SUA is unlikely to increase or reduce the risk of OP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wu, Li, Dai, Dai, Liu, Xu, Huang, Chi and Wang.)

Background: Extensive observational data suggest a link between celiac disease (CeD) and osteoporosis, but the causality and mediating mechanism remain undetermined. Herein, we performed a Mendelian randomization (MR) study to address these concerns., Methods: We obtained the summary-level statistics for CeD from a large genome-wide association study (GWAS) comprising 4,533 cases and 10,750 controls of European ancestry. The GWAS data for osteoporosis-related traits and inflammatory cytokines were derived from the UK Biobank, FinnGen, IEU OpenGWAS database, or GWAS catalog. Two-sample MR with the inverse variance-weighted methods were employed to evaluate the genetic association between CeD and osteoporosis-related traits. The potential inflammatory mediators from CeD to osteoporosis were explored using two-step mediation analyses., Results: The primary MR analyses demonstrated causal associations between genetically predicted CeD and osteoporosis (odds ratio [OR]: 1.110, 95% confidence interval [CI]: 1.043-1.182, p =0.001), total body bone mineral density (β: -0.025, p =0.039), and osteoporotic fracture (OR: 1.124, 95% CI: 1.009-1.253, p =0.034). Extensive sensitivity analyses consolidated these findings. Among the candidate inflammatory cytokines, only interleukin-18 was observed to mediate the effects of CeD on osteoporosis, with an indirect OR of 1.020 (95% CI: 1.000-1.040, p =0.048) and a mediation proportion of 18.9%. The mediation effects of interleukin-18 could be validated in other datasets (OR: 1.015, 95% CI: 1.001-1.029, p =0.041). Bayesian colocalization analysis supported the role of interleukin-18 in osteoporosis., Conclusion: The present MR study reveals that CeD is associated with an increased risk of developing osteoporosis, which may be partly mediated by upregulation of interleukin-18., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xiang, Zheng, Luo and Yang.)

Background: Osteoporosis (OP) is a chronic disease characterized by decreased bone mass, loss of skeletal structural integrity and increased susceptibility to fracture. Available studies have shown that the pyruvate dehydrogenase kinase (PDK) family is associated with osteoclastogenesis and bone loss, but the specific role of Pdk3 in bone pathology has not been systematically investigated., Methods: A cell OP model was established in receptor activator for nuclear factor- κ B Ligand (RANKL)-induced bone marrow macrophages (BMMs). Hereafter, the expression levels of Pdk3 and osteoclastogenesis feature genes including nuclear factor of activated T cells 1 ( Nfatc1 ), Cathepsin K ( Ctsk ), osteoclast associated Ig-like receptor ( Oscar ) in BMMs-derived osteoclasts were examined based on real-time quantitative PCR and western blotting methods. Further, the phosphorylation of ERK, P65 and JAK/STAT and their correlation was Pdk3 was gauged. In particular, changes in the activity of these signaling pathways were observed by silencing experiments of the Pdk3 gene (using small interfering RNA). Finally, the effects of Pdk3 gene silencing on signaling pathway activity, osteoclastogenesis, and related inflammatory and apoptotic indicators were observed by transfection with PDK3-specific siRNA., Results: Following RANKL exposure, the levels of Pdk3 and osteoclastogenesis feature genes were all elevated, and a positive correlation between Pdk3 and osteoclastogenesis feature genes was seen. Meanwhile, ERK, P65 and JAK/STAT phosphorylation was increased by RANKL, and Pdk3 was confirmed to be positively correlated with the phosphorylation of ERK, P65 and JAK/STAT. Additionally, in RANKL-exposed osteoclasts, Pdk3 knockdown diminished the phosphorylation of ERK, P65 and JAK/STAT, reduced the expressions of osteoclastogenesis feature genes. Importantly, knockdown of Pdk3 also reduced the expression of inflammatory cytokines and resulted in elevated levels of Bax and Casp3 expression, as well as downregulation of Bcl2 expression., Conclusion: This study reveals for the first time the role of Pdk3 in RANKL-induced osteoclastogenesis and OP. These findings provide a foundation for future studies on the role of Pdk3 in other bone diseases and provide new ideas for the development of OP therapeutics targeting Pdk3., Competing Interests: The authors declare there are no competing interests., (©2024 Zhang et al.)

Background: Osteoporosis (OP) and sarcopenia are prevalent musculoskeletal conditions among the elderly. Nevertheless, the causal relationship between sarcopenia and OP remains a subject of controversy and uncertainty. In this study, we employed cross-sectional analysis and Mendelian randomization (MR) to investigate the intricate relationship between sarcopenia and OP., Methods: The cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) spanning 1999-2020, which involved in 116,876 participants. It assessed the correlation between sarcopenia, osteoporosis (OP), and bone mineral density (BMD) using Chi-square tests, T-tests, and a multiple logistic regression model. Additionally, we conducted Mendelian randomization (MR) analysis to investigate the causal effects of sarcopenia-related characteristics (ALM) on OP. We employed IVW, sensitivity analysis, heterogeneity testing, and other methods for MR. The ALM data was sourced from the UK Biobank (n=450,243), while the aggregated data on OP was obtained from GWAS statistics (n=53,236)., Results: In this cross-sectional analysis, we observed that in the multivariate logistic regression model, without adjusting for any variables, OP emerged as a risk factor for sarcopenia [OR 95% CI = 1.90 (1.13-3.18), P = 0.02]. Following adjustments for gender, age, BMI, and biochemical variables, OP retained its status as a risk factor for sarcopenia [OR 95% CI = 3.54 (1.91-6.54), P < 0.001]. Moreover, after accounting for all variables, OP emerged as an independent risk factor for sarcopenia [OR 95% CI = 4.57 (1.47-14.22), P = 0.01].In the MR analysis, we uncovered that femoral neck BMD (FN BMD), lumbar spine BMD (LS BMD), and forearm bone mineral density (FA BMD) exerted a direct causal influence on ALM [FA BMD: OR 95% CI = 1.028 (1.008, 1.049), p = 0.006; FN BMD: OR (95% CI) = 1.131 (1.092, 1.170), p = 3.18E-12; LS BMD: OR (95% CI) = 1.080 (1.062, 1.098), p = 2.86E-19]., Conclusion: Our study has revealed a positive correlation between OP and the prevalence of sarcopenia. It suggests a potentially robust causal relationship between OP and sarcopenia. Notably, OP appears to be associated with a higher likelihood of losing ALM, and a significant loss of ALM may contribute to a decline in LS BMD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhu, Zeng, Shi, Qin, Liu, Yang, Qiu, Pan, An and Li.)

Osteoporosis, a common bone disease in older individuals, involves the progression influenced by N6-methyladenosine (m6A) modification. This study aimed to elucidate the effects of VDAC3 m6A modification on human bone mesenchymal stromal cell (BMSC) senescence and osteogenic differentiation. BMSCs were treated with etoposide to induce senescence. Senescence was assessed by β-galactosidase staining and quantitative real-time PCR (qPCR), and osteogenic differentiation was evaluated using Western blot, alkaline phosphatase, and alizarin red S staining. VDAC3 and ALKBH5 expression were quantified by qPCR, and their interaction was assessed by RNA immunoprecipitation (RIP) and luciferase reporter assay. m6A methylation was analyzed using the Me-RIP assay. VDAC3 expression was significantly decreased in etoposide-treated BMSCs (1.00 ± 0.13 vs. 0.26 ± 0.06). VDAC3 overexpression reduced etoposide-induced senescence and promoted osteogenic differentiation. ALKBH5 overexpression inhibited VDAC3 m6A modification (1.00 ± 0.095 vs. 0.233 ± 0.177) and its stability. ALKBH5 knockdown decreased etoposide-induced senescence and promoted osteogenic differentiation, effects that were reversed by VDAC3 knockdown. YTHDF1 was identified as the m6A methylation reader, and its overexpression inhibited VDAC3 stability. We demonstrated that ALKBH5 inhibited osteogenic differentiation of etoposide-induced senescent cells through the inhibition of VDAC3 m6A modification, and YTHDF1 acted as the m6A methylation reader. These findings provide a novel theoretical basis for the treatment of osteoporosis., (© 2024. The Author(s).)

Angiogenesis-osteogenesis coupling is critical for proper functioning and maintaining the health of bones. Any disruption in this coupling, associated with aging and disease, might lead to loss of bone mass. Osteoporosis (OP) is a debilitating bone metabolic disorder that affects the microarchitecture of bones, gradually leading to fracture. Computational analysis revealed that normal angiogenesis is disrupted during the progression of OP, especially postmenopausal osteoporosis (PMOP). The genes associated with OP and PMOP were retrieved from the DisGeNET database. Hub gene analysis and molecular pathway enrichment were performed via the Cytoscape plugins STRING, MCODE, CytoHubba, ClueGO and the web-based tool Enrichr. Twenty-eight (28) hub genes were identified, eight of which were transcription factors (HIF1A, JUN, TP53, ESR1, MYC, PPARG, RUNX2 and SOX9). Analysis of SNPs associated with hub genes via the gnomAD, I-Mutant2.0, MUpro, ConSurf and COACH servers revealed the substitution F201L in IL6 as the most deleterious. The IL6 protein was modeled in the SWISS-MODEL server and the substitution was analyzed via the YASARA FoldX plugin. A positive ΔΔG (1.936) of the F201L mutant indicates that the mutated structure is less stable than the wild-type structure is. Thirteen hub genes, including IL6 and the enriched molecular pathways were found to be profoundly involved in angiogenesis/endothelial function and immune signaling. Mechanical loading of bones through weight-bearing exercises can activate osteoblasts via mechanotransduction leading to increased bone formation. The present study suggests proper mechanical loading of bone as a preventive strategy for PMOP, by which angiogenesis and the immune status of the bone can be maintained. This in silico analysis could be used to understand the molecular etiology of OP and to develop novel therapeutic approaches., (© 2024. The Author(s).)

Background: Patients with osteoporosis (OP) are often associated with decreased hand grip strength and increased risk of falling. It remains unclear whether there is a genetic causal between hand grip strength and OP, falling risk., Methods: The Mendelian randomization study was used to investigate the genetic causal effect of low hand grip strength on total body bone mineral density (BMD) at different ages, OP, and falling risk. Genes for low hand grip strength, total body BMD at different ages, OP, and falling risk were obtained from published genome-wide association studies. Inverse variance weighted, MR-Egger, and weighted median were applied to perform the MR analysis. The Cochran's Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis were used to detect the pleiotropy or heterogeneity., Results: The results showed strong evidence that low hand grip strength was positively associated with OP (OR: 1.006, 95% CI: 1.003-1.010; P= 0.0001) and falling risk (OR: 1.069, 95% CI: 1.013-1.129; P= 0.0160), and could not directly affect the different ages of total body BMD (P> 0.05). There was no heterogeneity or horizontal pleiotropy in the sensitivity analysis (all P> 0.05)., Conclusion: The study found a positive causal relationship between low hand grip strength and higher risk of OP and falling, which should be taken into account in the development of future prevention and screening strategies for OP and falling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ma, Qiao, Wang, Pan and Guo.)

Weightlessness osteoporosis, which progresses continuously and has limited protective effects, has become one of the major problems that need to be solved in manned spaceflight. Our study aims to investigate the regulatory role of PHF8 in disuse osteoporosis by observing the expression of PHF8 in bone marrow mesenchymal stem cells (BMSCs) under simulated weightlessness conditions. Therefore, we used the model of ground-based microgravity simulated by disuse osteoporosis patients and tail suspension in mice to simulate microgravity in vivo, and measured the expression of PHF8 in bone tissue. Subsequently, we used the 2D gyroscope to simulate the weightless effect on bone marrow mesenchymal stem cells. In the weightless condition, we detected the proliferation, apoptosis, osteogenesis, and osteogenic differentiation functions of BMSCs. We also detected the expression of osteogenic-related transcription factors after knocking down and overexpressing PHF8. Our results show that the weightless effect can inhibit the proliferation, osteogenesis, and osteogenic differentiation functions of BMSCs, while enhancing their apoptosis; and overexpression of PHF8 can partially alleviate the osteoporosis caused by simulated weightlessness, providing new ideas and clues for potential drug targets to prevent weightlessness and disuse osteoporosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Recent evidence suggests an association between age-related osteoporosis and cellular senescence in the bone; however, the specific bone cells that play a critical role in age-related osteoporosis and the mechanism remain unknown. Results revealed that age-related osteoporosis is characterized by the loss of osteoblast Men1. Osteoblast-specific inducible knockout of Men1 caused structural changes in the mice bones, matching the phenotypes in patients with age-related osteoporosis. Histomorphometrically, Men1-knockout mice femurs decreased osteoblastic activity and increased osteoclastic activity, hallmarks of age-related osteoporosis. Loss of Men1 induces cellular senescence via mTORC1 activation and AMPK suppression, rescued by metformin treatment. In bone morphogenetic protein-indued bone model, loss of Men1 leads to accumulation of senescent cells and osteoporotic bone formation, which are ameliorated by metformin. Our results indicate that cellular senescence in osteoblasts plays a critical role in age-related osteoporosis and that osteoblast-specific inducible Men1-knockout mice offer a promising model for developing therapeutics for age-related osteoporosis., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Nephritis and osteoporosis are debilitating medical conditions that significantly impact human health and reduce quality of life. To develop potential therapeutic strategies for these disorders necessitates understanding the genetic and molecular mechanisms. Here, we employed bioinformatics techniques purposed to find key genes and associated pathways responsible for nephritis-osteoporosis comorbidity. Six microarray datasets of systemic lupus erythematosus (SLE) and osteoporosis were retrieved from the Gene Expression Omnibus (GEO) database. Post normalization of data sets LIMMA package was utilized for differential expression analysis, among the datasets 44 differentially expressed genes (DEGs) were identified. The identified 44 genes were further analyzed for gene ontology (GO) where it was found that these genes are involved in defense response, organism interactions, and response to external stimuli. In predicting the molecular function, they were involved in several biological processes including binding to lipopolysaccharides and having peptidase and hydrolase activities. Firstly, the identified genes were primarily associated with certain granules such as specific granules and secretory granules in the aspect of cellular components. Enrichment analysis pointed out the potential pathways linked to the immune system, neutrophil degranulation, innate immunity, and immune response to tuberculosis. To examine interactions among DEGs, a complex protein-protein interaction (PPI) network was built, resulting in the identification of seven hub genes, CXCL8, ELANE, LCN2, MMP8, IFIT1, MX1, and ISG15. The study suggests that these elucidated hub genes might have high potential to be exploited as promising biomarkers and therapeutic targets in nephritis-osteoporosis. Taken together, this study provided deeper insights into the genetic and molecular basis for the comorbidity of nephritis and osteoporosis., Competing Interests: Competing interests None., (Copyright © 2024 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Background: Osteoporosis and sarcopenia are common age-related conditions characterized by the progressive loss of bone density and muscle mass, respectively. Their co-occurrence, often referred to as osteosarcopenia, presents significant challenges in elderly care due to increased fragility and functional impairment. Existing studies have identified shared pathological mechanisms between these conditions, including inflammation, hormonal imbalances, and metabolic dysregulation, but a comprehensive understanding of their molecular interplay remains incomplete., Objective: This study aims to deepen our understanding of the molecular interactions between sarcopenia and osteoporosis through an integrated omics approach, revealing potential therapeutic targets and biomarkers., Methods: Employing a combination of proteomics and transcriptomics analyses, this study analyzed bone and muscle tissue samples from patients diagnosed with osteoporosis and osteosarcopenia. Techniques included high-throughput sequencing and label-free proteomics, supported by advanced bioinformatics tools for data analysis and functional annotation of genes and proteins., Results: The study found marked differences in gene and protein expressions between osteoporosis and osteosarcopenia tissues. Specifically, genes like PDIA5, TUBB1, and CYFIP2 in bone, along with MYH7 and NCAM1 in muscle, exhibited differential expression at both mRNA and protein levels. Pathway analyses revealed the significance of oxidative-reduction balance, cellular metabolism, and immune response in the progression of these conditions. Importantly, the study pinpointed osteoclast differentiation and NF-kappa B signaling pathways as critical in the molecular dynamics of osteosarcopenia, suggesting potential targets for therapy., Conclusions: This study utilized transcriptomics and proteomics to identify key genes and proteins impacting sarcopenia and osteoporosis, employing advanced network tools to delineate interaction networks and crucial signaling pathways. It highlighted genes like PDIA5 and TUBB1, consistently expressed in both analyses, involved in pathways such as osteoclast differentiation and cytokine interactions. These insights enhance understanding of the molecular interplay in bone and muscle degeneration with aging, suggesting directions for future research into therapeutic interventions and prevention strategies for age-related degenerative diseases., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Falls are the most common consequence of low bone mineral density (BMD). However, due to limitations inherent in observational studies, the causal relationship between the two remains unestablished., Methods: This study utilized Mendelian Randomization (MR) analysis to explore the causal relationship between BMD and the risk of falling, incorporating linkage disequilibrium score (LDSC) regression for genetic correlation assessment. The primary method was inverse-variance weighted (IVW), supplemented with sensitivity analyses and the causal analysis using summary effect estimates (CAUSE) to address heterogeneity and pleiotropy biases., Results: LDSC analysis indicated significant genetic correlations between BMD at various sites and falling risk (r g range: -0.82 to 0.76, all P < 0.05). IVW analysis, with False Discovery Rate (FDR) correction, showed a protective causal effect of total body BMD (OR = 0.85, 95% CI 0.82-0.88, P = 7.63 × 10 -17 , P FDR  = 1.91 × 10 -16 ), femoral neck BMD (OR = 0.81, 95% CI 0.75-0.88, P = 3.33 × 10 -7 , P FDR  = 5.55 × 10 -7 ), lumbar spine BMD (OR = 0.85, 95% CI 0.79-0.91, P = 9.56 × 10 -7 , P FDR  = 1.20 × 10 -6 ), and heel BMD (OR = 0.82, 95% CI 0.79-0.81, P = 1.69 × 10 -39 , P FDR  = 8.45 × 10 -39 ) on falling risk. No causal relationship was found for forearm BMD (OR = 1.02, 95% CI 0.94-1.11, P = 0.64, P FDR  = 0.64). Replication datasets and CAUSE analysis provided causal evidence consistent with the main findings., Conclusion: The study established a causal relationship between BMD at four different sites and the risk of falling, highlighting potential areas for targeted prevention strategies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study explores the molecular interplay between systemic lupus erythematosus (SLE) and osteoporosis (OP), aiming to uncover shared gene signatures and pathways for better treatment approaches. Leveraging microarray data from the Gene Expression Omnibus (GEO) database, we employed weighted gene coexpression network analysis to identify coexpression modules in SLE and OP, with subsequent protein-protein interaction analysis clarifying the connections among shared genes. Key genes were pinpointed using CytoHubba and random forest algorithms, validated across independent GEO datasets, and further analyzed through gene set enrichment analysis (GSEA) and immune infiltration studies. We discovered two highly correlated modules in SLE and OP, isolating 30 shared genes and identifying GBP1, SOCS1, IFI16, and XAF1 as central to both conditions. Notably, XAF1 and GBP1 mRNA levels were significantly elevated in the peripheral blood of SLE patients compared with healthy and RA counterparts, underscoring their potential as biomarkers. GSEA and immune infiltration analyses indicated pronounced immune and inflammatory responses, especially in interferon signaling pathways, implicating these core-shared gene networks in the diseases' pathogenesis. The findings highlight the involvement of GBP1, SOCS1, IFI16, and XAF1 in SLE with concurrent OP and suggest that targeting immune and inflammatory responses, particularly through interferon pathways, may offer therapeutic promise for these intertwined conditions., (© 2024 Wiley Periodicals LLC.)

Age-related osteoporosis is characterized by a marked decrease in the number of osteoblasts, which has been partly attributed to the senescence of cells of the osteoblastic lineage. Epigenetic studies have provided new insights into the mechanisms of current osteoporosis treatments and bone repair pathophysiology. N6-methyladenosine (m6A) is a novel transcript modification that plays a major role in cellular senescence and is essential for skeletal development and internal environmental stability. Bioinformatics analysis revealed that the expression of the m6A reading protein Igf2bp2 was significantly higher in osteoporosis patients. However, the role of Igf2bp2 in osteoblast senescence has not been elucidated. In this study, we found that Igf2bp2 levels are increased in ageing osteoblasts induced by multiple repetition and H 2 O 2 . Increasing Igf2bp2 expression promotes osteoblast senescence by increasing the stability of Slc1a5 mRNA and inhibiting cell cycle progression. Additionally, Mettl3 was identified as Slc1a5 m6A-methylated protein with increased m6A modification. The knockdown of Mettl3 in osteoblasts inhibits the reduction of senescence, whereas the overexpression of Mettl3 promotes the senescence of osteoblasts. We found that administering Cpd-564, a specific inhibitor of Mettl3, induced increased bone mass and decreased bone marrow fat accumulation in aged rats. Notably, in an OVX rat model, Igf2bp2 small interfering RNA delivery also induced an increase in bone mass and decreased fat accumulation in the bone marrow. In conclusion, our study demonstrated that the Mettl3/Igf2bp2-Slc1a5 axis plays a key role in the promotion of osteoblast senescence and age-related bone loss., Competing Interests: Declaration of competing interest No conflicts of interest have been declared by all authors., (Copyright © 2024. Published by Elsevier B.V.)

Purpose of the Review: Osteosarcopenia is a geriatric syndrome associated with disability and mortality. This review summarizes the key microRNAs that regulate the hallmarks of sarcopenia and osteoporosis. Our objective was to identify components similarly regulated in the pathology and have therapeutic potential by influencing crucial cellular processes in both bone and skeletal muscle., Recent Findings: The simultaneous decline in bone and muscle in osteosarcopenia involves a complex crosstalk between these tissues. Recent studies have uncovered several key mechanisms underlying this condition, including the disruption of cellular signaling pathways that regulate bone remodeling and muscle function and regeneration. Accordingly, emerging evidence reveals that dysregulation of microRNAs plays a significant role in the development of each of these hallmarks of osteosarcopenia. Although the recent recognition of osteosarcopenia as a single diagnosis of bone and muscle deterioration has provided new insights into the mechanisms of these underlying age-related diseases, several knowledge gaps have emerged, and a deeper understanding of the role of common microRNAs is still required. In this study, we summarize current evidence on the roles of microRNAs in the pathogenesis of osteosarcopenia and identify potential microRNA targets for treating this condition. Among these, microRNAs-29b and -128 are upregulated in the disease and exert adverse effects by inhibiting IGF-1 and SIRT1, making them potential targets for developing inhibitors of their activity. MicroRNA-21 is closely associated with the occurrence of muscle and bone loss. Conversely, microRNA-199b is downregulated in the disease, and its reduced activity may be related to increased myostatin and GSK3β activity, presenting it as a target for developing analogues that restore its function. Finally, microRNA-672 stands out for its ability to protect skeletal muscle and bone when expressed in the disease, highlighting its potential as a possible therapy for osteosarcopenia., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)