The Emerging Role of Osteocytes in Cancer in Bone

Abstract

Advances in the last decade have established the osteocyte, the most abundant cell in bone, as a dynamic and multifunctional cell capable of controlling bone homeostasis by regulating the function of both osteoblasts and osteoclasts. In addition, accumulating evidence demonstrates that osteocyte function is altered in several skeletal disorders, and targeting osteocytes and their derived factors improves skeletal health. Despite the remarkable progress in our understanding of osteocyte biology, there has been a paucity of information regarding the role of osteocytes in the progression of cancer in bone. Exciting, recent discoveries suggest that tumor cells communicate with osteocytes to generate a microenvironment that supports the growth and survival of cancer cells and stimulates bone destruction. This review features these novel findings and discussions regarding the impact of chemotherapy on osteocyte function and the potential of targeting osteocytes for the treatment of cancer in bone. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Keywords: BONE FORMATION; BONE RESORPTION; CANCER; MYELOMA; OSTEOCYTES.

Figure 1

Communication between cancer cells and osteocytes contributes to tumor progression and bone destruction. Cell‐to‐cell communication between osteocytes and myeloma cells results in bidirectional Notch signaling activation, leading to osteocyte apoptosis and stimulation of myeloma cell proliferation. In addition, osteocyte apoptosis leads to increased RANKL expression, which acts as a chemoattractant to recruit osteoclast precursors to local areas and promote their differentiation, thus initiating bone resorption. In addition, myeloma cells increase SOST/Sclerostin production by osteocytes, which in turn decreases Wnt signaling and inhibits osteoblast differentiation and function. Recent findings support that the beneficial effects of bisphosphonates and proteasome inhibitors in cancer patients are also due to the prevention of osteocyte (and osteoblast) apoptosis. In addition, preclinical data have shown that targeting the osteocyte‐derived factor Sclerostin stimulates osteoblast differentiation and new bone formation in bones infiltrated with cancer cells. Similarly, pharmacologic inhibition of RANKL, abundantly expressed by osteocytes in adult bone, prevents skeletal‐related events in cancer patients.