Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment

Although osteolysis is a common complication in patients with multiple myel oma (MM), the biologic mechanisms involved in the pathogenesis of MM-induce d bone disease are poorly understood. Two factors produced by stromal-osteo blastic cells seem critical to the regulation of bone resorption: osteoprot egerin (OPG) and its ligand (OPGL). OPGL stimulates osteoclast differentiat ion and activity, whereas OPG inhibits these processes. The present study i nvestigated whether myeloma cells affect physiologic OPG/ OPGL balance in t he bone marrow (BM) environment. Ten human myeloma cell lines and myeloma c ells isolated from 26 consecutive patients with MM failed to express OPGL a nd only rarely produced a low amount of OPG. In a coculture system, human m yeloma cells up-regulated OPGL expression but strongly downregulated OPG pr oduction in preosteoblastic (preOB) or stromal cells (BMSCs) of primary hum an BM at the mRNA and protein levels. This effect, which was dependent on c ell-to-cell contact between myeloma cells and BMSCs or preOB, partially inv olved the integrin VLA-4. In addition, overexpression of OPGL mRNA occurred in ex vivo BM cultures obtained from MM patients as compared with healthy donors, and immunohistochemical staining performed on BM biopsy specimens s howed an increase of OPGL and a reduction of OPG expression in MM patients as compared with healthy subjects. In summary, these data indicate that mye loma cells affect the OPG/OPGL ratio in the BM environment and tend to conf irm that the OPG/OPGL system is involved in the pathogenesis of MM-induced bone disease. (C) 2001 by The American Society of Hematology.