Autophagy modulates osteoarthritis-related gene expression in human chondrocytes

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 64; no. 6; pp. 1920 - 1928
• Main Authors: Sasaki, Hiroshi, Takayama, Koji, Matsushita, Takehiko, Ishida, Kazunari, Kubo, Seiji, Matsumoto, Tomoyuki, Fujita, Norifumi, Oka, Shinya, Kurosaka, Masahiro, Kuroda, Ryosuke
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.06.2012; Wiley; Wiley Subscription Services, Inc
• Subjects: Aged; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Autophagy; Autophagy - physiology; Beclin-1; Biological and medical sciences; Cartilage, Articular - drug effects; Cartilage, Articular - metabolism; Cells, Cultured; Chondrocytes - drug effects; Chondrocytes - metabolism; Chondrocytes - pathology; Diseases of the osteoarticular system; Female; Gene expression; Gene Expression - drug effects; Gene Expression - physiology; Humans; Kinases; Male; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Miscellaneous. Osteoarticular involvement in other diseases; Osteoarthritis; Osteoarthritis, Knee - genetics; Osteoarthritis, Knee - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Sirolimus - pharmacology; Human; Chondrocyte; Diseases of the osteoarticular system; Rheumatology; Arthropathy; Degenerative disease; Gene expression; Osteoarthritis
• ISSN: 0004-3591; 2326-5191; 1529-0131; 2326-5205
• DOI: 10.1002/art.34323

Objective Autophagy, an evolutionarily conserved process for the bulk degradation of cytoplasmic components, serves as a cell survival mechanism. The purpose of this study was to elucidate the role of autophagy in human chondrocytes and pathophysiology of osteoarthritis (OA). Methods Autophagy in articular cartilage and primary chondrocytes was assessed using antibodies for the autophagy markers light chain 3 and beclin 1. The states of autophagy under catabolic and nutritional stresses were examined. We also examined the effects of inhibition or induction of autophagy under stimulation with interleukin‐1β. Autophagy was inhibited by small interfering RNA targeting ATG5, and autophagy was induced by rapamycin. The effects of inhibition or induction of autophagy were examined by real‐time polymerase chain reaction for aggrecan, COL2A1, MMP13, and ADAMTS5 messenger RNA. To further examine the mechanism of autophagy regulation in OA human chondrocytes, we investigated whether autophagy modulates apoptosis and reactive oxygen species (ROS). Results Autophagy was increased in OA chondrocytes and cartilage. Catabolic and nutritional stresses increased autophagy. In addition, the inhibition of autophagy caused OA‐like gene expression changes, while the induction of autophagy prevented them. Furthermore, the inhibition of autophagy increased the amount of cleaved poly(ADP‐ribose) polymerase and cleaved caspase 9, while the induction of autophagy inhibited these increases. ROS activity was also decreased by induction of autophagy. Conclusion These observations suggested that increased autophagy is an adaptive response to protect cells from stresses, and that autophagy regulates OA‐like gene expression changes through the modulation of apoptosis and ROS. Further studies about autophagy in chondrocytes will provide novel insights into the pathophysiology of OA.