Finally, how myeloma lyses bone

For more than 25 years osteoclastic activation by myeloma tumor cells has been accepted as the explanation for the characteristic osteolytic lesions found in myeloma patients. But despite many suggested candidates, the activating factors involved have resisted definitive identification. In this issue 2 elegant studies together convincingly pin the blame for the osteolysis on an imbalance of 2 molecules, osteoprotegerin ligand (OPGL, aka TRANCE and RANKL) and osteoprotegerin (OPG). Both of these molecules are involved together in the regulation of bone resorption: OPGL, a member of the tumor necrosis factor superfamily, causes activation and differentiation of osteoclasts by binding to the receptor RANK on osteoclast precursors, and OPG is a decoy receptor and inhibitor of OPGL.

In the in vitro study by Giuliani and colleagues (page 3527), OPG and OPGL were shown to be expressed by osteoblast precursors and bone marrow stromal cells in myeloma marrow and not by the myeloma cells themselves. But culturing human myeloma cells in contact with stromal cells resulted in increased expression of OPGL mRNA. Conditioned medium from the myeloma cells did not stimulate OPGL expression, and the availability of the integrin VLA-4 was required for the increased expression. On the other hand, cocultures of myeloma cells and osteoblast precursors resulted in a decrease in OPG mRNA. Immunohistochemistry also revealed increased OPGL⁺ stromal cells and decreased OPG⁺ osteoblastic cells associated with myeloma cell infiltrates in marrow biopsies from patients with osteolytic lesions, as compared with those without bone lesions or to healthy controls, further supporting the authors' conclusion that an imbalance in the OPG/OPGL system induced by the myeloma tumor leads to osteolysis.

In the second study Croucher and colleagues (page 3534) examined the effect of recombinant human OPG on a mouse model of myeloma in which the mice develop severe osteolytic bone disease by 12 weeks after intravenous transfer of myeloma cells. Treatment with OPG was initiated once myeloma was established, as evidenced by detection of a serum paraprotein. Four weeks later, the OPG-treated mice had markedly reduced numbers of lytic bone lesions, decreased numbers of osteoclasts and increased bone density, as compared with the untreated myeloma mice. Unlike Giuliani and colleagues, Croucher and colleagues found that the mouse myeloma cells expressed RANKL (OPGL) mRNA and that the protein could be demonstrated on the cell membrane by flow cytometry. They leave open the possibility that stromal cell synthesis of RANKL (OPGL) may also be stimulated by the myeloma cells, as described by others. Clearly, these studies raise promising therapeutic possiblities for recombinant OPG and other approaches targeting RANKL (OPGL) to prevent and treat the devastating bone disease of multiple myeloma.