Abstract

 

Osteoarthritis (OA) is the most common form of arthritis and is a leading cause of disability with a large socioeconomic cost. OA is a whole-joint disease characterized by cartilage destruction, synovial inflammation, osteophyte formation, and subchondral bone sclerosis. To date, however, no effective disease-modifying therapies for OA have been developed. The estrogen-related receptors (ERRs), a family of orphan nuclear receptor transcription factors, are composed of ERR¥á, ERR¥â, and ERR¥ã, which play diverse biological functions such as cellular energy metabolism. However, the role of ERRs in OA pathogenesis has not been studied yet. Among the ERR family members, ERR¥ã is markedly upregulated in human and various models of mouse OA cartilage. Adenovirus-mediated overexpression of ERR¥ã in the mouse knee joint tissue caused OA pathogenesis. Additionally, cartilage-specific ERR¥ã transgenic (Tg) mice exhibited enhanced experimental OA. Consistently, ERR¥ã in articular chondrocytes directly caused expression of matrix metalloproteinase (MMP) 3 and MMP13, which play a crucial role in cartilage destruction. In contrast, genetic ablation of Esrrg or shRNA-mediated Esrrg silencing in the joint tissues abrogated experimental OA in mice. These results collectively indicated that ERR¥ã is a novel catabolic regulator of OA pathogenesis and can be used as a therapeutic target for OA.