Regulation of osteoprotegerin pro- or anti-tumoral activity by bone tumor microenvironment

Tumor development in bone is often associated with fractures, bone loss and bone pain, and improvement is still needed in therapeutic approaches. Bone tumors are related to the existence of a vicious cycle between bone resorption and tumor proliferation in which the molecular triad osteoprotegerin (OPG)/receptor activator of NF-kappaB (RANK)/RANK ligand (RANKL) plays a pivotal role. RANKL, a member of the TNF superfamily, is one of the main inducers of bone resorption. Its soluble receptor OPG represents a promising therapeutic candidate as it prevents bone lesions and inhibits associated tumor growth. However, its therapeutic use in bone tumors remains controversial due to its ability to bind and inhibit another member of the TNF superfamily, TNF related apoptosis inducing ligand (TRAIL), which is a potent inducer of tumor cell apoptosis. Through its heparin binding domain, OPG is also able to bind proteoglycans present in the bone matrix. This paper is an overview of the involvement of the micro-environment, as represented by the balance of RANKL/TRAIL and the presence of proteoglycans in the regulation of OPG biological activity in bone tumors.