Estrogen-related receptor γ (errγ) is a catabolic regulator of osteoarthritis pathogenesis

Abstract

Purpose: The estrogen-related receptor (ERR) family of orphan nuclear receptor is composed of ERRα, ERRβ and ERRγ, which are known to regulate various isoform-specific functions under normal and pathophysiological conditions. However, the functions of ERRs in regulating joint cartilage homeostasis and/or OA pathogenesis have not yet been studied. Here, we investigate the involvement of ERRs in the pathogenesis of osteoarthritis (OA) in mice. Methods: Human OA cartilage was sourced from individuals undergoing arthroplasty. C57BL/6J mice were used for the experimental OA studies. Esrrg+/- mice (B6.129P2-Esrrgtm1Dgen/Mmnc) were purchased from the Mutant Mouse Regional Resource Center (MMRRC). Col2a1-Esrrg Tg mice were generated using the Col2a1 promoter and enhancer. Human OA cartilage was frozen, sectioned at a thickness of 5 μm, and fixed in paraformaldehyde. Sulfate proteoglycans were detected by alcian blue staining, and cartilage destruction in mice was examined using safranin-O staining. Femoral condyles and tibial plateaus were obtained from mice, and chondrocytes were isolated from cartilage tissue by digestion with 0.2% collagenase. Results: Among the ERR family members, ERRγ was specifically upregulated in cartilage from human OA patients and various mouse models of OA. Gain-of-function (adenovirus-mediated overexpression in joint tissues or Col2a1-Esrrg Tg mice) and loss-of-function (Esrrg+/- mice or shRNA-mediated knockdown) approaches clearly indicated that ERRγ acts as a novel catabolic regulator of OA pathogenesis, at least in part, by the upregulating matrix-degrading enzymes, MMP3 and MMP13, in articular chondrocytes. Conclusions: Our results are the first to demonstrate that ERRγ acts as a catabolic regulator of cartilage degeneration and OA pathogenesis, and collectively support the idea that ERRγ could be a therapeutic target for OA