Li Fangyu, Cui Shun
Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Biol Chem. 2025 May;301(5):108500. doi: 10.1016/j.jbc.2025.108500. Epub 2025 Apr 9.
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.
补体系统在生理发育过程中的骨骼生长和骨骼稳态中发挥着重要作用。然而，补体C3a受体（C3aR）对与年龄相关的骨质流失的具体影响仍不清楚。在本研究中，我们发现C3aR表达随年龄增长而增加，且在对照小鼠中与衰老分子p53、p21和p16的表达情况相同。敲低C3aR可降低衰老标志物的表达，并显著改善骨衰老。值得注意的是，敲低小鼠体内的C3aR可有效逆转年龄诱导的骨质流失，其特征为成骨细胞数量增加和破骨细胞数量减少。在D - 半乳糖诱导的衰老体外模型中，C3aR表达增加与衰老标志物如p53、p21和p16的表达增加相关。用C3aR拮抗剂（JR14a）处理成功减弱了这些细胞衰老标志物的表达，并降低了晚期凋亡细胞的比例。从机制上讲，JR14a处理通过激活YAP1/β - 连环蛋白信号通路减轻了D - 半乳糖介导的对前成骨细胞成骨分化的抑制作用。在D - 半乳糖诱导的衰老小鼠模型中，用JR14a处理可改善骨微结构和骨质流失。总之，这些研究揭示了C3aR在调节骨骼稳态中的作用，表明靶向C3aR可能是治疗与年龄相关的骨质疏松症的一种有前景的治疗策略。
