Inhibition of receptor activator of nuclear factor kappa-B ligand pathway for the management of aggressive osteosarcoma

Ioannis Panagiotidis, Dimitrios Christoulas, Evangelos Terpos


Receptor activator of nuclear factor kappa-B ligand (RANKL) is a member of the tumor necrosis factor receptor superfamily and is considered the most important factor for osteoclastogenesis. RANKL is encoded by a gene, which is found at chromosome 13q14 and is expressed mainly by osteocytes, activated T-cells and bone marrow stromal cells. Alternative splicing of the RANKL mRNA results either in the expression of a type-II transmembrane glycoprotein or in the expression of a soluble ligand. Soluble RANKL may also be produced from its transmembrane state by the function of metalloproteinases. RANKL acts through its binding to the receptor RANK which is on the surface of mature osteoclasts but also of osteoclast precursors and chondrocytes. The RANKL/RANK binding induces the activity of mature osteoclasts, while it inhibits their apoptosis. Furthermore, the binding of RANKL to RANK enhances the differentiation of osteoclast precursors, their fusion and the formation of mature osteoclasts through the NF-κB, c-fos and Jun N-terminal kinase pathways (1). RANKL is implicated in the pathogenesis of bone loss in several disorders including osteoporosis, malignant disorders (bone metastases of solid tumors and multiple myeloma) as well as metabolic bone diseases (1-3). Osteoprotegerin (OPG) is the decoy receptor of RANKL which is produced mainly by the osteoblasts and is often elevated to balance the RANKL overexpression in several bone malignancies. Among primary bone tumors, RANKL expression and the RANKL/OPG ratio were very high in giant cell tumor of the bone, while high RANKL mRNA expression was observed in cases of osteosarcoma, chondrosarcoma, and enchondroma, as compared to cases of multiple myeloma and bone lesions from metastatic cancer (4). More specifically for osteosarcoma, the expression of RANK and RANKL was tested in 91 human osteosarcomas tumor samples. Sixty-three osteosarcomas (69%) expressed RANK, while only 8 cases (9%) expressed RANKL. Interestingly, the expression of RANK was significantly associated with shorter disease-free survival and worse response to chemotherapy, while RANKL expression was more frequent in osteosarcoma of the lower extremity than in any other location (5). These data suggest that inhibiting RANKL seems to be a logical approach for the management of primary bone tumors. To-date, the only inhibitor of RANKL that has entered to clinical development, denosumab, has been licensed not only for the treatment of bone metastases due to solid tumors but also for the management of giant cell tumor of the bone. However, there is no data for the efficacy of denosumab in osteosarcoma patients.