Estrogen-related receptor γ causes osteoarthritis by upregulating extracellular matrix-degrading enzymes

The estrogen-related receptor (ERR) family of orphan nuclear receptor is composed of ERR alpha, ERR beta, and ERR gamma, which are known to regulate various isoform-specific functions under normal and pathophysiological conditions. Here, we investigate the involvement of ERRs in the pathogenesis of osteoarthritis (OA) in mice. Among ERR family members, ERR gamma is markedly upregulated in cartilage from human OA patients and various mouse models of OA. Adenovirus-mediated overexpression of ERR gamma in mouse knee joint or transgenic expression of ERR gamma in cartilage leads to OA. ERR gamma overexpression in chondrocytes directly upregulates matrix metalloproteinase (MMP)-3 and MMP13, which are known to play crucial roles in cartilage destruction in OA. In contrast, genetic ablation of Esrrg or shRNA-mediated downregulation of Esrrg in joint tissues abrogates experimental OA in mice. Our results collectively indicate that ERR gamma is a novel catabolic regulator of OA pathogenesis.