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.
The aim of this study was to examine exercise-related genes in articular cartilage identified through bioinformatics analysis to dissect the potential signaling pathway involved in mechanical stimulation in osteoarthritis (OA). To this end, we evaluated the GSE74898 dataset from the Gene Expression Omnibus database for exercise-related differentially expressed miRNAs (DE-miRNAs) using the R software package and predicted potential target genes for these miRNAs using miRTarBase. Functional annotation and pathway enrichment analysis were performed for these potential DE-miRNA targets. The effects of mechanical stimulation on the tumor necrosis factor-related apoptosis-induced ligand (TRAIL)/nuclear factor-kappa B (NF-κB)/nucleotide-binding and oligomerization domain-like receptor containing protein 3 (NLRP3) signaling pathway were evaluated in articular cartilage and chondrocytes. A total of 394 DE-miRNAs were identified (103 upregulated miRNAs; 291 downregulated miRNAs) in the cartilage of rats following treadmill exercise compared to the cartilage of unexercised control rats. Thus, mechanical stimulation could modulate the TRAIL/NF-κB/NLRP3 signaling pathway on OA. Histological and protein analysis demonstrated that moderate-intensity treadmill exercise could ameliorate OA through the downregulation of TRAIL. Furthermore, moderate cyclic tensile strain (CTS) could rescue chondrocytes from the effects of TRAIL via the inhibition of the nuclear translocation of NF-κB p65 and formation of NLRP3. Our findings indicate that moderate mechanical stimulation could ameliorate the degeneration of cartilage and chondrocyte damage through the inhibition of the TRAIL/NF-κB/NLRP3 pathway.
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