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Estrogen-related receptor ャ is a novel catabolic regulator of osteoarthritis pathogenesis
Young-Ok Son1, Jang-Soo Chun1,*
1National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sci, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
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メ, ERRモ, and ERRャ, 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ャ is markedly upregulated in human and various models of mouse OA cartilage. Adenovirus-mediated overexpression of ERRャ in the mouse knee joint tissue caused OA pathogenesis. Additionally, cartilage-specific ERRャ transgenic (Tg) mice exhibited enhanced experimental OA. Consistently, ERRャ 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ャ is a novel catabolic regulator of OA pathogenesis and can be used as a therapeutic target for OA.
Abstract, Accepted Manuscript [Submitted on January 25, 2018, Accepted on January 25, 2018]
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