JUNB-FBXO21-ERK axis promotes cartilage degeneration in osteoarthritis by inhibiting autophagy
Open Access
- 1 February 2021
- journal article
- research article
- Published by Wiley in Aging Cell
- Vol. 20 (2), e13306
- https://doi.org/10.1111/acel.13306
Abstract
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-1 beta, tumor necrosis factor-alpha, 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.Funding Information
- National Natural Science Foundation of China (81272050, 81772420)
This publication has 38 references indexed in Scilit:
- OsteoarthritisThe Lancet, 2015
- Regulation of the Catabolic Cascade in Osteoarthritis by the Zinc-ZIP8-MTF1 AxisCell, 2014
- Combination of MEK-ERK inhibitor and hyaluronic acid has a synergistic effect on anti-hypertrophic and pro-chondrogenic activities in osteoarthritis treatmentJournal of Molecular Medicine, 2012
- Evolution of semi-quantitative whole joint assessment of knee OA: MOAKS (MRI Osteoarthritis Knee Score)Osteoarthritis and Cartilage, 2011
- Autophagy and cartilage homeostasis mechanisms in joint health, aging and OANature Reviews Rheumatology, 2011
- Role of proinflammatory cytokines in the pathophysiology of osteoarthritisNature Reviews Rheumatology, 2010
- The OARSI histopathology initiative – recommendations for histological assessments of osteoarthritis in the ratOsteoarthritis and Cartilage, 2010
- Improving Bioscience Research Reporting: The ARRIVE Guidelines for Reporting Animal ResearchPLoS Biology, 2010
- Osteoarthritic cartilage chondrocytes alter subchondral bone osteoblast differentiation via MAPK signalling pathway involving ERK1/2Bone, 2010
- International Cartilage Repair Society (ICRS) and Oswestry macroscopic cartilage evaluation scores validated for use in Autologous Chondrocyte Implantation (ACI) and microfractureOsteoarthritis and Cartilage, 2007