Irisin Mitigates Oxidative Stress, Chondrocyte Dysfunction and Osteoarthritis Development through Regulating Mitochondrial Integrity and Autophagy

Antioxidants, vol. 9, pp. 810

Abstract

Compromised autophagy and mitochondrial dysfunction downregulate chondrocytic activity, accelerating the development of osteoarthritis (OA). Irisin, a cleaved form of fibronectin type III domain containing 5 (FNDC5), regulates bone turnover and muscle homeostasis. Little is known about the effect of Irisin on chondrocytes and the development of osteoarthritis. This study revealed that human osteoarthritic articular chondrocytes express decreased level of FNDC5 and autophagosome marker LC3-II but upregulated levels of oxidative DNA damage marker 8-hydroxydeoxyguanosine (8-OHdG) and apoptosis. Intra-articular administration of Irisin further alleviated symptoms of medial meniscus destabilization, like cartilage erosion and synovitis, while improved the gait profiles of the injured legs. Irisin treatment upregulated autophagy, 8-OHdG and apoptosis in chondrocytes of the injured cartilage. In vitro, Irisin improved IL-1β-mediated growth inhibition, loss of specific cartilage markers and glycosaminoglycan production by chondrocytes. Irisin also reversed Sirt3 and UCP-1 pathways, thereby improving mitochondrial membrane potential, ATP production, and catalase to attenuated IL-1β-mediated reactive oxygen radical production, mitochondrial fusion, mitophagy, and autophagosome formation. Taken together, FNDC5 loss in chondrocytes is correlated with human knee OA. Irisin repressed inflammation-mediated oxidative stress and extracellular matrix underproduction through retaining mitochondrial biogenesis, dynamics and autophagic program. Our analyses shed new light on the chondroprotective actions of this myokine, and highlight the remedial effects of Irisin on OA development.

Authors 13

1. Feng‐Sheng Wang

   Chang Gung University · Kaohsiung Chang Gung Memorial Hospital

   Affiliation as printed

   Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

   Core Laboratory for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

   Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

   Graduate Institute of Clinical Medical Science, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan

2. Chung-Wen Kuo

   Kaohsiung Chang Gung Memorial Hospital

   Affiliation as printed

   Core Laboratory for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

   Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

3. Jih‐Yang Ko

   Kaohsiung Chang Gung Memorial Hospital

   Affiliation as printed

   Department of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

4. Yushan Chen

   Kaohsiung Chang Gung Memorial Hospital

   Affiliation as printed

   Core Laboratory for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

   Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

5. Shaoyu Wang

   Kaohsiung Chang Gung Memorial Hospital

   Affiliation as printed

   Core Laboratory for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

   Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

6. Huei-Jing Ke

   Kaohsiung Chang Gung Memorial Hospital

   Affiliation as printed

   Core Laboratory for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

   Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

7. Pei-Chen Kuo

   Kaohsiung Chang Gung Memorial Hospital

   Affiliation as printed

   Core Laboratory for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

   Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

8. Chin-Huei Lee

   Kaohsiung Chang Gung Memorial Hospital

   Affiliation as printed

   Core Laboratory for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

   Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

9. Jian‐Ching Wu

   Kaohsiung Chang Gung Memorial Hospital

   Affiliation as printed

   Biobank and Tissue Bank, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

10. Wen‐Bin Lu

    National Sun Yat-sen University

    Affiliation as printed

    Institute of Biomedical Sciences, National Sun Yat-Sun University, Kaohsiung 804, Taiwan

11. Ming‐Hong Tai

    National Sun Yat-sen University

    Affiliation as printed

    Institute of Biomedical Sciences, National Sun Yat-Sun University, Kaohsiung 804, Taiwan

12. Holger Jahr corresponding Aachen Department of Anatomy and Cell Biology

    Maastricht University Medical Centre · Maastricht University · Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Department of Anatomy and Cell Biology, University Hospital RWTH Aachen, 52074 Aachen, Germany

    Department of Orthopedic Surgery, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands

13. Wei‐Shiung Lian corresponding

    Kaohsiung Chang Gung Memorial Hospital

    Affiliation as printed

    Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

    Core Laboratory for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

    Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan