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

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‐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.

Mechanical Stimulation Protects Against Chondrocyte Pyroptosis Through Irisin-Induced Suppression of PI3K/Akt/NF-κB Signal Pathway in Osteoarthritis

“…Twelve donors participated in our study and we obtained informed consent from all of our patients. As mentioned in our previous study ( Lin et al, 2021 ), the cartilage and the clinicopathological features of patients with knee osteoarthritis after total knee replacement were collected and divided into damaged and undamaged groups according to the International Cartilage Repair Society (ICRS) grade ( Kleemann et al, 2005 ), ICRS = 0 was classified as the undamaged region, and the ICRS = 1 ∼ 4 was classified as the damaged region. We compared the damaged area with the undamaged area in the same donors.…”

“…Using imaging techniques, we quantified the tibial plateau or femoral condyle surface by calculating the ratio of the lesion area to the total surface area. Both the tibial and femoral joints were evaluated based on a maximum score of 10 ( Gerwin et al, 2010 ; Kohn et al, 2016 ; Lin et al, 2021 ). The scoring was performed by two experienced observers who were blinded to the study groups.…”

Primary Repair for Treating Acute Proximal Anterior Cruciate Ligament Tears: A Histological Analysis and Prospective Clinical Trial

“…The paraffin-embedded tissues were cut into 5-μM thick sections and stained with haematoxylin and eosin (HE) or toluidine blue stain for evaluation. Finally, the modified Mankin scoring system was used to analyse osteoarthritis (OA)-like changes in the knee joints of the rabbits ( Lin et al, 2021 ).…”

Adipokine Signaling Pathways in Osteoarthritis

“…Although ERK½ MAPK has no direct impact on the degradation of the extracellular matrix like p38 MAPK and JNK MAPK, it mainly mediates the proliferation and hypertrophic differentiation of chondrocytes, leading to cartilage calcification and osteophyte formation ( Lin et al, 2021 ). As the only cell of articular cartilage, the fate of chondrocytes determines the formation and development of adipokine-associated OA.…”