Fig. 2.

Bone destruction by factors over-produced by MM cells and/or their surrounding microenvironment in bone in MM. MM cells enhance osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells (BMSCs), leading to skewing of the cellular microenvironment in the bone marrow. Cytokines aberrantly over-produced by MM cells, including MIP-1, HGF and IL-34 as well as MM cell adhesion (VLA4/5-VCAM-1) up-regulate RANKL and IL-6 production in BMSCs to enhance osteoclastogenesis and MM cell growth/survival. Osteoclasts enhance MM cell growth/survival. MM cells enhance angiogenesis in concert with osteoclasts. In addition, factors over-produced by MM cells and/or their surrounding microenvironment in bone such as soluble Wnt inhibitors, IL-3, IL-7, TNF-α, activin A and TGF-β suppress osteoblastic differentiation. RANKL and sclerostin are over-produced by osteocytes. Therefore, multiple factors act together to eventually develop extensive bone destruction along with MM tumor expansion