| Bone remodeling is controlled by a balance between bone formation and bone resorption. Osteoclasts, regulated by hormones, growth factors, and cytokines, are the primary cell type responsible for bone resorption. The newly identified receptor activator of NFκB ligand (RANKL), its receptor RANK, and its decoy receptor osteoprotegerin (OPG) have introduced a mechanism that is critical for differentiation and activation of osteoclasts. Dysregulation of this system is associated with bone pathophysiology, however, its role in ethanol-induced osteoporosis and osteolytic metastases of prostate cancer (CaP) is unknown.; To investigate the role of OPG in alcohol-mediated osteoporosis, we measured bone remodeling parameters in mice that were either on a control diet, an ethanol diet, or an ethanol diet plus OPG administration. OPG diminished the ethanol-induced (1) decrease in bone mineral density; (2) decrease in cancellous bone volume and trabecular width; (3) increase in urinary deoxypyridinolines; and (4) increase in colony forming unit-granulocyte monocyte (CFU-GM) formation and osteoclastogenesis. These data demonstrate that OPG diminishes ethanol-induced bone loss through its ability to abrogate ethanol-induced osteoclastogenesis.; Another disease that may be associated with osteoclastogenesis is CaP skeletal metastases. CaP forms osteoblastic lesions with an underlying osteoclastic component. However, the importance of osteoclastogenesis in the development of CaP skeletal lesions is unknown. We demonstrated that CaP cells directly induce osteoclastogenesis in the absence of underlying stroma in vitro . CaP cells produce soluble RANKL, which may account for this CaP-mediated osteoclastogenesis. To evaluate the importance of osteoclastogenesis on CaP tumor development in vivo, CaP cells were injected both intratibially and subcutaneously into the same mice, followed by administration of OPG. OPG completely prevented establishment of mixed osteolytic/osteoblastic tibial tumors that were observed in the vehicle-treated animals, but had no effect on subcutaneous tumor growth. Consistent with the role of osteoclasts in tumor development, osteoclast numbers were elevated at bone:tumor interface in the vehicle-treated mice compared to the normal values in the OPG-treated mice. These results emphasize the important role that osteoclast activity plays in the establishment of CaP skeletal metastases.; We conclude that alcohol and CaP skeletal metastases induce osteoclastogenesis through RANKL, which can be inhibited by OPG. |
