p66shc siRNA Nanoparticles Ameliorate Chondrocytic Mitochondrial Dysfunction in Osteoarthritis

Abstract

Hyo Jung Shin,1,2 Hyewon Park,1,2 Nara Shin,1,2 Juhee Shin,1,2 Do Hyeong Gwon,1,2 Hyeok Hee Kwon,1,3 Yuhua Yin,1,2 Jeong-Ah Hwang,1,2 Jinpyo Hong,2 Jun Young Heo,1,4,5 Cuk-Seong Kim,1,6 Yongbum Joo,7 Youngmo Kim,7 Jinhyun Kim,8 Jaewon Beom,9 Dong Woon Kim1,2 1Department of Medical Science, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea; 2Department of Anatomy and Cell Biology, Brain Research Institute, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea; 3Department of Pediatrics; 4Biochemistry; 5Infection Control Convergence Research Center; 6Physiology Chungnam National University College of Medicine, Daejeon, Republic of Korea; 7Department of Orthopedics, Chungnam National University College of Medicine, Daejeon, Republic of Korea; 8Division of Rheumatology, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea; 9Department of Rehabilitation Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Republic of KoreaCorrespondence: Dong Woon Kim DVM., PhD.Department of Anatomy and Cell Biology, Chungnam National University College of Medicine, 266 Munhwa-Ro, Chung-Gu, Daejeon 35015, Republic of KoreaTel [phone]Fax [phone]Email [email protected] Kim, MD., PhD.Department of Internal Medicine, Chungnam National University College of Medicine, 266 Munhwa-Ro, Chung-Gu, Daejeon 35015, Republic of KoreaTel [phone]Fax [phone]Email [email protected]: Osteoarthritis (OA) is the most common type of joint disease associated with cartilage breakdown. However, the role played by mitochondrial dysfunction in OA remains inadequately understood. Therefore, we investigated the role played by p66shc during oxidative damage and mitochondrial dysfunction in OA and the effects of p66shc downregulation on OA progression.Methods: Monosodium iodoacetate (MIA), which is commonly used to generate OA animal models, inhibits glycolysis and biosynthetic processes in chondrocytes, eventually causing cell death. To observe the effects of MIA and poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles, histological analysis, immunohistochemistry, micro-CT, mechanical paw withdrawal thresholds, quantitative PCR, and measurement of oxygen consumption rate and extracellular acidification rate were conducted.Results: p-p66shc was highly expressed in cartilage from OA patients and rats with MIA-induced OA. MIA caused mitochondrial dysfunction and reactive oxygen species (ROS) production, and the inhibition of p66shc phosphorylation attenuated MIA-induced ROS production in human chondrocytes. Inhibition of p66shc by PLGA-based nanoparticles-delivered siRNA ameliorated pain behavior, cartilage damage, and inflammatory cytokine production in the knee joints of MIA-induced OA rats.Conclusion: p66shc is involved in cartilage degeneration in OA. By delivering p66shc-siRNA-loaded nanoparticles into the knee joints with OA, mitochondrial dysfunction-induced cartilage damage can be significantly decreased. Thus, p66shc siRNA PLGA nanoparticles may be a promising option for the treatment of OA.Keywords: osteoarthritis, monosodium iodoacetate, p66shc, ROS, mitochondrial dysfunction, PLGA-based nanoparticles

Keywords

• osteoarthritis
• monosodium iodoacetate
• p66shc
• ros
• mitochondrial dysfunction
• plga-based nanoparticles