Bone Marrow Monocyte/Macrophage Derived Activin A Mediates the Osteoclastogenic Effects of IL-3 in Myeloma

Myeloma bone disease is characterized by tremendous bone destruction with suppressed bone formation. IL-3 is a multifunctional cytokine that increases myeloma cell growth and osteoclast proliferation while inhibiting osteoblast differentiation. While IL-3 appears to be an attractive therapeutic target for myeloma, attempts at targeting IL-3 have been unsuccessful due to IL-3’s effects on normal hematopoiesis. Thus identification of IL-3’s downstream effects in MMBD is important for effective targeting of this cytokine in MM. Here we demonstrated that treatment of myeloma patient CD14+ bone marrow monocyte / macrophages with IL-3 induces high levels of Activin A (ActA), a pluripotent TGF-β superfamily member that, like IL-3, modulates MMBD by enhancing osteoclastogenesis and inhibiting osteoblasts. We show that IL-3 induced osteoclastogenesis is mediated by ActA and is RANKL independent. Additionally, IL-3 induced ActA secretion is greatest early in osteoclastogenesis and ActA acts early in osteoclastogenesis. Therefore we suggest that therapies targeting ActA production should block IL-3’s effects in myeloma bone disease. Investigate the mediators of IL-3’s effects on bone remodeling in myeloma we performed gene expression profiling using Affymetrix GeneChip analysis of IL-3 treated CD14+ peripheral blood from healthy donor.