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Glycosaminoglycans as Potential Regulators of Osteoprotegerin Therapeutic Activity in Osteosarcoma

¹ Institut National de la Sante et de la Recherche Medicale ERI 7; ² Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives; ³ Institut National de la Sante et de la Recherche Medicale U892; ⁴ Université de Nantes, IFR26; ⁵ In-Cell-Art; ⁶ CHU, Hôtel Dieu, Nantes, France and ⁷ Institut National de la Sante et de la Recherche Medicale UMR 484, Clermont-Ferrand, France

Requests for reprints: Françoise Rédini, EA 3822-Institut National de la Sante et de la Recherche Medicale ERI7, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Faculté de Médecine, 1 rue Gaston Veil, 44035 Nantes cedex 1, France. Phone: 33-272-641-143; Fax: 33-240-412-860; E-mail: francoise.redini{at}univ-nantes.fr.

Key Words: osteoprotegerin • glycosaminoglycan • TRAIL • RANKL • osteosarcoma

Osteosarcoma is the most frequent primary bone malignant tumor that develops mainly in children and adolescents. Despite recent improvements in chemotherapy and surgery, survival rate is 50% after 5 years. Osteoprotegerin (OPG) is a potent inhibitor of osteoclast differentiation and activation, but its use as therapeutic agent in cancer-associated osteolysis remains controversial due to its ability to bind and inhibit the apoptotic effect of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) on tumor cells. The therapeutic effects of full-length OPG (1-401) and OPG 1-194 lacking its heparin-binding domain delivered by nonviral gene therapy were compared in a murine model of osteolytic osteosarcoma. Tumor incidence, progression, and associated bone lesions were significantly diminished in the OPG 1-194 group, but not in the OPG 1-401 group, compared with controls. As receptor activator of nuclear factor-B ligand (RANKL), TRAIL, and glycosaminoglycans (GAG) were shown to be overexpressed in osteosarcoma environment compared with control tissue, OPG 1-401 bioactivity may be modulated by one of these protagonists. Surface plasmon resonance analyses performed with OPG, TRAIL, and GAGs revealed that TRAIL binds both forms of OPG with the same affinity. In addition, as OPG 1-194 and OPG 1-401 similarly inhibit TRAIL-induced apoptosis, it suggests that TRAIL is not involved in the modulation of OPG bioactivity. However, as GAGs inhibit OPG 1-401 but not OPG 1-194 binding to TRAIL or to RANKL, they may represent potent regulators of OPG availability and antitumor activity in bone tumor microenvironment. [Cancer Res 2009;69(2):526–36]

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