PGRMC2 influences the onset of postmenopausal osteoporosis through disulfidptosis in monocytes: Evidence from experimental validation and Mendelian randomization

This study explores the role of disulfidptosis in monocytes and its relation to postmenopausal osteoporosis (PMOP). Using single-cell RNA sequencing and microarray assays, we identified key genes: LONRF1, ACAP2, IPO9, and PGRMC2. Through differential analysis, Weighted Gene Co-expression Network Analysis (WGCNA), and machine learning, these genes were linked to PMOP. Functional enrichment and ROC curve analysis demonstrated their effectiveness in distinguishing postmenopausal fracture patients from healthy individuals. Notably, PGRMC2 exhibited significant expression differences, highlighted by a notable Area Under the Curve (AUC) value of 0.665. Further investigation involved Western blotting and immunohistochemical assays, revealing decreased PGRMC2 expression in ovariectomized (OVX) mice. This decrease was consistent across both experimental methods, emphasizing PGRMC2's role in PMOP. Moreover, PGRMC2 was predominantly present in macrophages compared to monocytes within bone tissue and was significantly located in bone marrow mesenchymal stem cells (BM-MSCs) in PMOP patients. It was also abundantly found in osteoblasts and adipocytes. Additionally, a Mendelian randomization analysis using the TwoSampleMR R package, with data from decode and GWAS databases, was conducted. This analysis showed a significant impact of PGRMC2 on osteoporosis risk (p = 0.0048, OR = 0.6836), suggesting a potential protective effect against the disease. Our results suggest that PGRMC2 may facilitate the differentiation of monocytes into macrophages in bone tissue, influencing the behavior of BM-MSCs. This, in turn, could impact the progression and severity of PMOP. The study provides new insights into the molecular mechanisms underlying postmenopausal osteoporosis and highlights the potential of PGRMC2 as a therapeutic target or biomarker for this condition.