Abstract
Osteoporosis is the most common metabolic bone disease in postmenopausal women. As precursors of osteoclasts, peripheral blood mononuclear cells are accessible and considered suitable models for studying osteoporosis pathology. Ubiquitination is a crucial protein degradation system in bone metabolism. The aim of this study was to identify potential ubiquitination-related genes in PBMCs that are related to osteoporosis pathogenesis. Therefore, we performed an integrated analysis of osteoporosis-related microarray datasets. With the obtained ubiquitination-related gene set, weighted gene coexpression network analysis was performed. The results showed that genes in the turquoise module were correlated with menopause, and 48 genes were identified as hub genes. A differential expression analysis revealed 43 differentially expressed genes between pre- and postmenopausal samples. After integrating the information on differentially expressed menopause-related genes, we found that several members of the ubiquitin-specific protease (USP) family (USP1, USP7, USP9X, USP16, and USP25) were highly expressed in samples from postmenopausal female and that, USP25 expression was significantly higher in low-BMD samples than in high-BMD samples among samples from premenopausal subjects (p = 0.0013) and among all samples (p = 0.013). Finally, we verified the protein expression of USP25 in PBMCs by performing Western blot analysis, which yielded results consistent with the aforementioned results. Moreover, by assessing GTEx datasets, we found that USP25 expression was highly correlated with TRAF6 expression in whole blood (p < 0.001). We also tested the protein expression levels of TRAF6 in PBMCs and found that it was positively correlated with USP25 expression (p = 0.036). Our results reveal that the ubiquitin-specific protease family may play important roles in menopause and that USP25 is related to osteoporosis pathogenesis.
Highlights
Osteoporosis (OP) is a systemic bone disease characterized by decreased bone mineral density (BMD) and increased fracture risk (Sambrook and Cooper 2006)
The results indicated that ubiquitinspecific protease 25 (USP25) may be an important ubiquitination gene in menopause and OP
The results showed that the log(k) of a node with connection degree k was negatively correlated with the log (P(k)) of node probability with a correlation coefficient greater than 0.8, indicating that the coexpression network conformed to a scalefree network
Summary
Osteoporosis (OP) is a systemic bone disease characterized by decreased bone mineral density (BMD) and increased fracture risk (Sambrook and Cooper 2006). Since estrogen profoundly regulates the metabolism of bone cells, postmenopausal osteoporosis (PMOP) with estrogen deficiency is the most typical form of OP (Eastell et al, 2016). Researchers have analyzed the effects of estrogen on bone metabolism, the mechanism underlying the development of PMOP is still not thoroughly understood (Anagnostis et al, 2021), and comprehensive treatment strategies for PMOP are lacking. The posttranslational modification mediated by the ubiquitinproteasome system (UPS) plays very important roles in protein localization, metabolism, regulation and degradation, and is essential for the balance between bone formation and bone resorption (Thibaudeau and Smith 2019; Shen et al, 2021). The interaction between estrogen and estrogen receptor a (ERα) can trigger posttranslational modification of ERα through interplay with signaling pathways to promote transcriptional activation and ubiquitin-mediated ERα proteolysis (Zhou and Slingerland 2014). Approximately 2 E1, 35 E2, and more than 600
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