Cellular communication and interplay in the bone microenvironment in myeloma bone disease

Interplay within the cells of the bone marrow microenvironment is responsible for the excessive bone destruction and abnormal bone remodeling that characterize multiple myeloma bone disease. Myeloma cells directly stimulate osteoclast formation through the production of osteoclast activating factors (OAFs) such as RANKL, MIP-1 alpha, IL-3, TNF alpha, Sema4D, and PTHrP. Physical interaction between myeloma cells and marrow stromal cells increases factors that enhance osteoclastogenesis, including RANKL, M-CSF, IL-6, and TNF alpha, and decrease production of osteoclast inhibitory factors, such as OPG. Newly formed osteoclasts secrete soluble factors such as osteopontin, MIP-1 alpha, IL-6, AXII, BAFF, and APRIL that stimulate tumor growth and increase the bone destructive process. Bone resorption releases matrix-associated growth factors such as TGF beta, IGFs, FGF, PDGFs, and BMPs that increase myeloma cell proliferation, exacerbating the osteolytic process. Myeloma cells also induce osteocyte apoptosis, which upregulates the expression of RANKL. Myeloma is characterized by a profound suppression of bone formation by myeloma-derived osteoblast-inhibitory factors that include DKK-1, sclerostin, HGF, IL-7, and TNF alpha. The inhibitory effects on bone formation are further increased by myeloma-induced release of sclerostin from osteocytes and TNF alpha from marrow stromal cells. Myeloma cells also induce marrow stromal cells to produce factors, including IL-6, VCAM-1, VEGF, and IGF-1, that support myeloma cell proliferation. Angiogenesis is also enhanced in multiple myeloma bone disease. Increased osteoclast activity appears to contribute to the increased angiogenesis via osteoclast secretion of angiogenic factors, such as osteopontin and MMP-9, and VEGF produced by multiple myeloma and stromal cells.