Osteoprotegerin inhibits prostate cancer–induced osteoclastogenesis and prevents prostate tumor growth in the bone

Abstract

IntroductionProstate cancer is the most frequently diagnosed cancer in men and the second leading cause of cancer death among men in the US. The most common site of prostate cancer metastasis is the bone, with up to 84% of patients demonstrating skeletal metastases (1). While initially thought to be primarily osteoblastic, it is now recognized that prostate cancer skeletal metastases have an extensive bone resorptive component (2, 3) that is caused primarily by osteoclasts (4). This accounts, in part, for the ability of bisphosphonates, which are antiosteoclastogenic agents, to diminish osteolysis, decrease pain, and improve mobility in patients with prostate cancer skeletal metastasis (5). However, the mechanisms through which prostate cancer skeletal metastases induce osteolytic lesions are not defined.The presence of an osteolytic component in prostate cancer skeletal metastases suggests that osteoclastogenesis may play a role in the establishment of these lesions. Recently, the discovery and characterization of a novel cytokine system -the TNF family member, receptor activator of NF-κB ligand (RANKL, also called OPGL, TRANCE, and ODF); its receptor, receptor activator of NF-κB (RANK, also called ODAR); and its decoy receptor, osteoprotegerin (OPG, also called OCIF and TR1) -has established a common mechanism through which osteoclastogenesis is regulated in normal bone (reviewed in ref. 6). RANKL, a transmembrane molecule located on bone marrow stromal cells and osteoblasts, binds to RANK, which is located on the surface of osteoclast precursors. This ligand-receptor interaction activates NF-κB, which stimulates differentiation of osteoclast precursors to osteoclasts. OPG, also produced by osteoblasts/stromal cells, binds to RANKL, sequestering it from binding to RANK, which results in inhibition of osteoclastogenesis. The requirement for RANKL to induce osteoclastogenesis suggests that it may mediate the osteolytic component of prostate cancer skeletal lesions. However, it is currently unknown if prostate cancer uses the Prostate cancer (CaP) forms osteoblastic skeletal metastases with an underlying osteoclastic component. However, the importance of osteoclastogenesis in the development of CaP skeletal lesions is unknown. In the present study, we demonstrate that CaP cells directly induce osteoclastogenesis from osteoclast precursors in the absence of underlying stroma in vitro. CaP cells produced a soluble form of receptor activator of NF-κB ligand (RANKL), which accounted for the CaP-mediated osteoclastogenesis. To evaluate for the importance of osteoclastogenesis on CaP tumor development in vivo, CaP cells were injected both intratibially and subcutaneously in the same mice, followed by administration of the decoy receptor for RANKL, osteoprotegerin (OPG). OPG completely prevented the establishment of mixed osteolytic/osteoblastic tibial tumors, as were observed in vehicle-treated animals, but it had no effect on subcutaneous tumor growth. Consistent with the role of osteoclasts in tumor development, oste...

RANKL acts directly on RANK‐expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes

“…Pharmacological inhibition of RANKL using recombinant constructs of either OPG-Fc or RANK-Fc in these models reduces tumor induced osteoclast numbers [18,[36][37][38].…”

Comparison of Fc-osteoprotegerin and zoledronic acid activities suggests that zoledronic acid inhibits prostate cancer in bone by indirect mechanisms

“…1 Inhibitors of bone resorption such as bisphosphonates (BPs), osteoprotegerin (OPG), and metalloproteinase (MMP) inhibitors have been reported to decrease bone resorption associated with bone metastasis and decrease tumor burden in several animal models. [2][3][4][5][6] BPs are currently used to treat osteoporosis, reduce bone metabolic activity in Paget's disease, and control metastatic breast cancer and associated osteolytic bone lesions, as well as metastatic CaP. In a clinical study Diel et al 7 reported that clodronate, a first-generation BP, decreased numbers of both bone and soft tissue metastases in breast cancer patients, suggesting potential direct effects of BPs on metastases in addition to decreased bone lysis in vivo.…”

In vitro blockade of receptor activator of nuclear factor‐κB ligand prevents osteoclastogenesis induced by neuroblastoma cells

“…Our current understanding of the pathogenesis of bone metastasis is that various osteotropic malignancies use RANKL-mediated mechanisms to trigger osteoclastic bone resorption. [13][14][15] Michigami et al 16 found that cell interaction between neuroblastoma cells and bone marrow of immunocompromised mice induced RANKL expression in host cells, leading to osteoclast formation and bone metastasis. However, apart from the above-mentioned work, the molecular mechanisms responsible for metastatic osteolysis in neuroblastoma have been poorly investigated, and the exact nature of neuroblastoma-bone interactions remains largely unknown.…”