Complement C3a promotes the formation of osteoclasts by inhibiting Sirt1 to activate the PI3K/PDK1/SGK3 pathway in patients with multiple myeloma

作者：Fengjuan Jiang, Yunhe Zhang, Fengping Peng, Hui Liu, Kai Ding, Panpan Cao, Xiaohan Liu, Lijuan Li, Zhaoyun Liu, Rong Fu · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-06319-3 · 被引用次数：5 · 研究领域：Multiple Myeloma Research and Treatments、Bone Metabolism and Diseases、Complement system in diseases

BACKGROUND: Myeloma bone disease (MBD) is the most common complication of multiple myeloma (MM). Our previous study showed that the complement C3a activates osteoclasts to participate in the pathogenesis of MBD; however, its mechanism of action is diverse and complex. Studies have shown that the Sirtuin (Sirt) family of proteins (i.e., Sirt1-7) are expressed in human bone and cartilage, and participate in bone metabolic balance. METHODS AND RESULTS: We measured the levels of complement C3a, Sirt1, osteoclast-related genes, and bone disease-related biological indicators using enzyme-linked immunosorbent assay (ELISA), quantitative real-time PCR and western blotting. Sirt1 expression in osteoclasts was observed to be lower in patients with MM compared to healthy donors and negatively correlated with complement C3a levels, osteoclast-related gene expression, and osteolysis-related markers. Co-immunoprecipitation (Co-IP) and immunostaining were used to verify the interaction between C3a and Sirt1 in RAW264.7 cells. Osteoclasts were then induced from bone marrow mononuclear cells (BMMCs) in patients with MM or cultured RAW264.7 cells, using C3a and/or Sirt1 activator (SRT1720)/inhibitors (EX527) in vitro. Sirt1 inhibits osteoclast formation and complement C3a reverses this inhibitory function of Sirt1 to activate osteoclasts. RAW264.7 cells with induced overexpression or knockdown Sirt1 were transfected with plasmid or shRNA, and RNA-seq analysis was performed. Increased Sirt1 exp...