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Estrogen-related receptor γ is a novel catabolic regulator of osteoarthritis pathogenesis

  • Son, Young-Ok (National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology) ;
  • Chun, Jang-Soo (National Creative Research Initiatives Center for Osteoarthritis Pathogenesis and School of Life Sciences, Gwangju Institute of Science and Technology)
  • Received : 2018.01.17
  • Published : 2018.04.30

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 $ERR{\alpha}$, $ERR{\beta}$, and $ERR{\gamma}$, 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, $ERR{\gamma}$ is markedly upregulated in human and various models of mouse OA cartilage. Adenovirus-mediated overexpression of $ERR{\gamma}$ in the mouse knee joint tissue caused OA pathogenesis. Additionally, cartilage-specific $ERR{\gamma}$ transgenic (Tg) mice exhibited enhanced experimental OA. Consistently, $ERR{\gamma}$ 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 $ERR{\gamma}$ is a novel catabolic regulator of OA pathogenesis and can be used as a therapeutic target for OA.

Keywords

Cartilage;Estrogen-related receptor ${\gamma}$;Interleukin-6;Matrix metalloproteinases;Osteoarthritis

Acknowledgement

Supported by : National Research Foundation of Korea, Korea Health Industry Development Institute

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