Osteoprotegerin inhibits osteoclast formation and bone resorbing activity in giant cell tumors of bone

Osteolysis is a common complication of tumors that arise in, or metastasize to, bone. The recent discovery of key regulators of osteoclast formation a nd activity, including receptor activator of nuclear factor of KB Ligand (R ANKL), RANK, and osteoprotegerin (OPG), may facilitate new treatment regime s for certain tumors associated with excessive bone loss. We recently showe d that the stromal cells of osteolytic giant cell tumors (GCT) of bone expr ess high levels of mRNA encoding RANKL, relative to mRNA for the RANKL anta gonist, OPG, compared with the expression patterns of other lytic and nonly tic bone tumors. In this study, we found that expression of RANKL and OPG m RNA continued by the stromal element of these tumors in a constitutive mann er for at least 9 days in the absence of giant cells, Immunostaining of unf ractionated GCT cultured in vitro revealed punctate cytoplasmic/membranous staining for RANKL and both cytoplasmic and extracellular matrix staining f or OPG in stromal cells. Giant cells (osteoclasts) were negative for RANKL staining, but stained brightly for cytoplasmic OPG protein, We also investi gated the functional relevance of these molecules for GCT osteolysis by add ing recombinant OPG and RANKL to cultured GCT cells. We found that OPG trea tment potently and dose-dependently inhibited resorption of bone slices by GCT, and could also inhibit the formation of multinucleated osteoclasts fro m precursors within the GCT, These effects of OPG were reversed by stoichio metric concentrations of exogenous RANKL, These data indicate that both the processes of osteoclast formation and activation in GCT are promoted by RA NKL. Therefore, GCT represent a paradigm for the direct stimulation of oste oclast formation and activity by tumor stromal cells, in contrast to the me chanisms described for osteolytic breast tumors and multiple myeloma, The d emonstration of these relationships is important in developing approaches t o limit tumor-induced osteolysis, (Bone 28:370-377; 2001) (C) 2001 by Elsev ier Science Inc. All rights reserved.