Blood, 15 December 2001, Vol. 98, No. 13, pp. 3503-3504
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.
Geraldine P. Schechter
Washington VA Medical Center
