RANKL signaling in bone physiology and cancer

Abstract

Increased osteoclast activity plays an operative role in the pathophysiology of skeletal complications of malignancy. This review focuses on the critical roles of a triad of molecules - receptor activator of nuclear factor kappa beta ligand and its two receptors, receptor activator of nuclear factor kappa beta and osteoprotegerin - in the regulation of osteoclastogenesis across a broad spectrum of cancer-induced bone diseases. While it is well established that osteoclastic bone resorption plays an operative role in the skeletal complications of 'osteolytic' bone metastasis, recent evidence has described osteoclasts in osteoblastic prostate cancer metastases and increases in serum markers of bone resorption in these patients. In addition to its essential role in osteoclastogenesis, receptor activator of nuclear factor kappa beta ligand has also been recently shown to increase migration and invasive properties of receptor activator of nuclear factor kappa beta-positive tumor cells, and potentially may play a direct role in the bone tropism of those tumors. The critical role of receptor activator of nuclear factor kappa beta ligand signaling in regulating osteoclast activity is described in detail in this review, as is its role in cancer-mediated bone destruction, and the potential of receptor activator of nuclear factor kappa beta ligand inhibition as a novel treatment in tumor-induced bone disease.