Cmpk2 regulates mitochondrial function in glucocorticoid-induced osteoblast senescence and affects glucocorticoid-inhibited osteoblast differentiation

Abstract

Mitochondrial dysfunction plays a crucial role in the development of glucocorticoid-induced osteoporosis (GIO). Cytidine monophosphate kinase 2 (Cmpk2), an essential mitochondria-associated gene, promotes the production of free mitochondrial DNA, which leads to the formation of inflammasome-mediated inflammatory factors. However, the specific role of Cmpk2 in GIO remains unclear. In this study, we report that glucocorticoids induce cellular senescence within the bone, particularly in bone marrow mesenchymal stem cells and preosteoblasts. We discovered that glucocorticoids cause mitochondrial dysfunction in preosteoblasts, increasing cellular senescence. Moreover, we observed elevated expression of Cmpk2 in preosteoblasts following glucocorticoid exposure. Inhibiting Cmpk2 expression alleviates glucocorticoid-induced cellular senescence and promotes osteogenic differentiation by improving mitochondrial function. Our study uncovers new mechanisms underlying glucocorticoid-induced senescence in stem cells and preosteoblasts, highlighting the potential of inhibiting the mitochondrial gene Cmpk2 to reduce senescence and enhance osteogenic differentiation. This finding offers a potential therapeutic approach for the treatment of GIO.