Postmenopausal osteoporosis (PMOP) is a prevalent condition among postmenopausal women, closely linked to estrogen deficiency, aging, and oxidative stress. Cellular senescence, through mechanisms such as the senescence-associated secretory phenotype (SASP) and bone marrow stromal cells (BMSCs) differentiation imbalance, disrupts bone homeostasis in PMOP. Macrophages play a critical role in maintaining bone homeostasis. However, the extent of macrophage senescence in PMOP and the mechanisms by which it disrupts bone homeostasis have not yet been elucidated. Eldecalcitol (ED-71), a novel drug, has shown potential in osteoporosis treatment, though its effects on macrophage are not fully elucidated. In this study, using hydrogen peroxide (H₂O₂), we induced senescence in macrophages and assessed senescence-associated markers by SA-β-gal staining, Western blotting, and RT-qPCR. We then employed an indirect co-culture system to investigate the paracrine impact of these senescent macrophages on the osteogenic differentiation of BMSCs. The PMOP model was established using ovariectomy (OVX) in mice, followed by histological evaluation. Both 17β-Estradiol (E2) and ED-71 effectively reduced cellular senescence-related indicators such as p16, p53 and β-galactosidase in macrophages, suggesting E2 can alleviate macrophage senescence, and ED-71 may serve as an alternative. Co-culture systems revealed that senescent macrophages impaired BMSCs osteogenic differentiation, an effect reversed by ED-71. SIRT1 inhibition with EX-527 disrupted ED-71's anti-senescence action. Additionally, ED-71 improved bone mass and aging in OVX mice. In conclusion, ED-71 alleviates macrophage senescence via the SIRT1/PGC-1α signaling axis, thereby enhancing BMSC osteogenic potential and mitigating bone loss in OVX-induced osteoporosis.
Keywords: 17β-estradiol; Eldecalcitol; Macrophage senescence; Osteoporosis; SIRT1/PGC-1α signaling pathway.
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