C-reactive protein promotes bone destruction in human myeloma through the CD32–p38 MAPK–Twist axis

Jing Yang, Zhiqiang Liu, Huan Liu, Jin He, Jianling Yang, Pei Lin, Qiang Wang, Juan Du, Wencai Ma, Zheng Yin, Eric Davis, Robert Z Orlowski, Jian Hou, Qing Yi

Bone destruction is a hallmark of myeloma and affects 80% of patients. Myeloma cells promote bone destruction by activating osteoclasts. In investigating the underlying mechanism, we found that C-reactive protein (CRP), a protein secreted in increased amounts by hepatocytes in response to myeloma-derived cytokines, activated myeloma cells to promote osteoclastogenesis and bone destruction in vivo. In mice bearing human bone grafts and injected with multiple myeloma cells, CRP bound to surface CD32 (also known as FcγRII) on myeloma cells, which activated a pathway mediated by the kinase p38 MAPK and the transcription factor Twist that enhanced the cells' secretion of osteolytic cytokines. Furthermore, analysis of clinical samples from newly diagnosed myeloma patients revealed a positive correlation between the amount of serum CRP and the number of osteolytic bone lesions. These findings establish a mechanism by which myeloma cells are activated to promote bone destruction and suggest that CRP may be targeted to prevent or treat myeloma-associated bone disease in patients.