CircFOXK2 Promotes the Progression of Osteoarthritis by Regulating the miR-4640-5p/NOTCH2 Axis.

ABSTRACT

OBJECTIVE: Osteoarthritis (OA) is the most common age-related chronic and disabling joint disease, frequently causing pain and disability in the adult population. Given that there are no proven disease-modifying drugs for OA, it is urgent to gain a deeper understanding of OA pathogenesis. This study intended to uncover the circFOXK2 regulation in OA. METHODS: Firstly, in vitro OA cell model was constructed by treating murine chondrocytes with interleukin (IL)-1ß. Then, a series of functional assays were conducted to evaluate the effect of circFOXK2 on OA progression in murine chondrocytes. Bioinformatics analysis and mechanism investigations were performed to investigate the competitive endogenous RNA (ceRNA) network of circFOXK2 in OA. RESULTS: CircFOXK2 is overexpressed in IL-1ß-treated chondrocyte. We confirmed the cyclic structure and cytoplasmic distribution of circFOXK2. Functionally, circFOXK2 promotes chondrocyte apoptosis and extracellular matrix (ECM) degradation but inhibiting chondrocyte proliferation. Mechanically, circFOXK2 competitively binds to microRNA-4640-5p (miR-4640-5p) to enhance NOTCH2 expression in OA, affecting OA progression. Besides, circFOXK2 could motivate the Notch pathway to accelerate OA progression. CONCLUSION: CircFOXK2/miR-4640-5p/NOTCH2 axis stimulates the Notch pathway to promote the transcription of inflammatory cytokines (IL33, IL17F and IL6), consequently facilitating OA progression in murine chondrocytes.