RANKL/RANK/osteoprotegerin system as novel therapeutic target in the treatment of primary bone tumors and osteolytic metastases

Primary bone tumors and cancers that metastasize to bone require osteoclastic activity to release tumor-supportive growth factors from bone tissue. A number of systemic and locally acting factors are known to influence osteoclast formation, fusion, activation, and survival. Recently, two critical extracellular regulators of osteoclast differentiation and activation have been identified: receptor activator of nuclear factor (NF-kappaB) ligand (RANKL) and osteoprotegerin (OPG). RANKL is a tumor necrosis factor (TNF)-related cytokine that stimulates osteoclast differentiation from hematopoietic precursor cells and activation of mature osteoclasts. RANKL activates its specific receptor, receptor activator of NF- kappaB (RANK), located on osteoclasts, chondrocytes and dendritic cells. Binding of the RANK ligand to its receptor and osteoclastogenesis are prevented by osteoprotegerin, a decoy receptor produced by osteoblasts and marrow stromal cells. The balance between RANKL and OPG is of major importance in bone homeostasis. Disorders of the RANKL/RANK/OPG system have been linked to several human diseases, including primary bone tumors skeletal metastases, and hypercalcemia of malignancy. The discovery and characterization of RANKL, RANK and OPG and subsequent studies have changed the concepts of bone metabolism and may form the basis of innovative therapeutic strategies. Novel treatment strategies for bone tumors are emerging based on blockade of the RANKL/RANK interaction. The advantage of these strategies is their potential to selectively target tumor cells. Combining these new strategies with currently available treatments such as chemotherapy and radiation therapy is under investigation, with promising results