C-Reactive Protein Promotes Bone Destruction in Human Myeloma By Stimulating Myeloma Cell Production of Osteolytic Cytokines Via the CD32/FcγRII-p38MAPK-Twist Axis

Abstract

More than 80% of patients with multiple myeloma develop bone destruction that causes pathological fractures, severe bone pain, spinal cord compression, and hypercalcemia. The normally balanced act between bone-resorbing osteoclasts and bone-forming osteoblasts is disrupted in those patients. It is well established that myeloma cells mediate bone destruction by activating osteoclasts. Studies have been shown that myeloma cells produce a number of cytokines such as nuclear factor kappa-B ligand (RANKL), macrophage inflammatory protein (MIP)-1α, and monocyte chemoattractant protein (MCP)-1, which increase osteoclast differentiation and bone resorption activity. Yet the mechanism how myeloma cells are regulated to do so is unknown. Here we show that C-reactive protein (CRP), a protein secreted in elevated amounts by hepatocytes in response to myeloma-derived cytokines, may be responsible for activating myeloma cells to promote osteoclastogenesis and inducing bone destruction in vivo. Using both SCID and SCID-hu models, we found that injection of human CRP into myeloma-bearing, but not myeloma-free, mice accelerated the induction of bone destruction in both murine and human bones, and significantly more osteoclasts were detected in the bone-tumor interface in CRP-injected mice as compared with controls. Mechanistic studies show that CRP binds to surface CD32/FcγRII, activates p38MAPK-twist pathways, and upregulates the secretion of osteolytic cytokines by myeloma cells. Furthermore, clinical studies revealed a highly positive correlation between the level of serum CRP and the number of osteolytic bone lesions in newly diagnosed myeloma patients. These findings establish a novel mechanism by which myeloma cells are activated to promote bone destruction in patients and suggest that CRP may be targeted to prevent or treat myeloma-associated bone disease. DisclosuresYang:Poseida Therapuetics: Research Funding; Cellectis: Research Funding. Orlowski:BioTheryX: Consultancy, Membership on an entity's Board of Directors or advisory committees.