JUNB‐FBXO21‐ERK axis promotes cartilage degeneration in osteoarthritis by inhibiting autophagy

• Published in: Aging cell Vol. 20; no. 2; pp. e13306 - n/a
• Main Authors: Lin, Zhiming, Miao, Jianing, Zhang, Tao, He, Ming, Wang, Ziyuan, Feng, Xinyuan, Bai, Lunhao
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.02.2021; John Wiley and Sons Inc
• Subjects: Age; Aging; Apoptosis; Arthritis; Autophagy; Binding sites; Body mass index; Cartilage; cartilage degeneration; Cartilage diseases; Chondrocytes; Cytokines; Degeneration; ERK; Extracellular signal-regulated kinase; FBXO21; Gender; Immunoprecipitation; JUNB; JunB protein; Kinases; Ligases; Lipopolysaccharides; Magnetic resonance imaging; Mass spectroscopy; Metabolism; Obesity; Original; Osteoarthritis; Overweight; Pathogenesis; Patients; Phagocytosis; Physiological aspects; Proteins; rats; Tumor necrosis factor; Tumor necrosis factor-TNF; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; autophagy; osteoarthritis; cartilage degeneration; metabolism; rats; FBXO21; JUNB; ERK
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13306

Osteoarthritis (OA) is a heterogeneous disease that is extremely hard to cure owing to its complex regulation network of pathogenesis, especially cartilage degeneration. FBXO21 is a subunit of ubiquitin E3 ligases that degrades P‐glycoprotein and EID1 by ubiquitination and activates the JNK and p38 pathways; however, its role in OA remains unknown. Here, the main objective of this study was to evaluate the potential effects and mechanism of FBXO21 in OA degeneration, we revealed that FBXO21 is upregulated in the cartilage of patients with OA, aging, and monosodium iodoacetate‐induced OA rats, and chondrocytes treated with interleukin‐1β, tumor necrosis factor‐α, and lipopolysaccharide. Moreover, the in vivo and in vitro knockdown of FBXO21 suppressed OA‐related cartilage degeneration, as evidenced by activated autophagy, upregulated anabolism, alleviated apoptosis, and downregulated catabolism. In contrast, its overexpression promoted OA‐related cartilage degeneration. In addition, using mass spectrometry and co‐immunoprecipitation assay, we demonstrated that the downstream mechanism of FBXO21 inhibits autophagy by interacting with and phosphorylating ERK. Furthermore, FBXO21 alleviated anabolism and enhanced apoptosis and catabolism by inhibiting autophagy in rat chondrocytes. Interestingly, for its upstream mechanism, JUNB promoted FBXO21 expression by directly targeting the FBXO21 promoter, thus further accelerating cartilage degeneration in SW1353 cells and rat chondrocytes. Overall, our findings reveal that the JUNB‐FBXO21‐ERK axis regulates OA apoptosis and cartilage matrix metabolism by inhibiting autophagy. Therefore, FBXO21 is an attractive target for regulating OA pathogenesis, and its knockdown may provide a novel targeted therapy for OA. FBXO21 is upregulated in osteoarthritis (OA). Knockdown and overexpression of FBXO21 suppresses and promotes OA‐related degeneration, respectively. Mechanistically, FBXO21 inhibits autophagy by interacting with and phosphorylating ERK, and enhances OA‐related degeneration by inhibiting autophagy. JUNB regulates FBXO21 expression via targeting FBXO21 promoter and accelerates OA‐related degeneration by promoting FBXO21.