Knockdown of C3aR alleviates age-related bone loss via activation of YAP1/β-catenin signaling

The complement system plays an important role in bone growth during physiological development and skeletal homeostasis. However, the specific impact of the complement C3a receptor (C3aR) on age-related bone loss remains unclear. In this study, we found that C3aR expression increased with age and was the same as that of the senescent molecules p53, p21, and p16 in control mice. Knockdown of C3aR reduced the expression of senescence markers and significantly ameliorated bone senescence. Notably, C3aR knockdown in mice effectively reversed age-induced bone loss, which was characterized by an increase in the number of osteoblasts and a decrease in the number of osteoclasts. In an in vitro model of D-gal-induced senescence, increased expression of C3aR correlated with increased expression of senescence markers such as p53, p21, and p16. Treatment with a C3aR antagonist (JR14a) successfully attenuated the expression of these markers of cellular senescence and reduced the proportion of late apoptotic cells. Mechanistically, JR14a treatment mitigated D-gal-mediated inhibition of osteoblastic differentiation in preosteoblasts through activation of the YAP1/β-catenin signaling pathway. In the D-gal-induced aging mouse model, treatment with JR14a ameliorates bone microarchitecture and bone loss. In summary, these studies revealed a role for C3aR in regulating bone homeostasis, suggesting that targeting C3aR may be a promising therapeutic strategy for the treatment of age-related osteoporosis.