HIF-2α as a possible therapeutic target of osteoarthritis

Objective: Endochondral ossification, a conversion process from nonvascularized and hypoxic cartilage to highly vascularized bone, plays a crucial role in osteoarthritis (OA) development as well as in physiological skeletal growth. We have shown that hypoxia-inducible factor-2 alpha (HIF-2 alpha, encoded by EPAS1) is an extensive regulator of the endochondal ossification process. Here we review the possible signaling network regulating OA development on the axis of HIF-2 alpha. Methods: Peer reviewed publications published prior to August 2010 were searched in the Pubmed database. Articles that were relevant to HIF and molecular mechanisms of the endochondral ossification and OA were selected. Results: As a trigger of OA, mechanical stress may induce the upstream NF-kappa B signal and HIF-2 alpha expression in joint cartilage of mice and humans, which causes transactivation of endochondral ossification-related molecules with the most potent beta-subunit partner aryl hydrocarbon nuclear translocator-like (ARNTL). In contrast to HIF-2 alpha, HIF-1 alpha functions to maintain cartilage via a distinct mechanism, so that the shifting of the HIFs might possibly be involved in an OA pathogenesis. Conclusion: Signals on the HIF-2 alpha axis from NF-kappa B signaling to the endochondral ossification-related molecules, possibly in combination with HIF-2 alpha and ARNTL, may represent a rational therapeutic target for OA with minimal effects on physiological skeletal homeostasis. (C) 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.