miR‐219a‐5p inhibits the pyroptosis in knee osteoarthritis by inactivating the NLRP3 signaling via targeting FBXO3

Abstract

Purpose This work was to identify the function and mechanism of miR‐219a‐5p in regulating knee osteoarthritis (KOA). Methods Rat fibroblast‐like synoviocytes (FLSs) were isolated to construct KOA cell model by lipopolysaccharide and adenosine triphosphate treatment. miR‐219a‐5p and FBXO3 expression in FLSs was modulated by transfection. Flow cytometry was executed to research FLSs apoptosis. Caspase‐1 and IL‐1β expression in FLSs was researched by immunofluorescence. The binding between miR‐219a‐5p and FBXO3 was identified by dual luciferase reporter gene assay. KOA rat model and miR‐219a‐5p up‐modulation KOA rat model were constructed. Step size of rats was analyzed. Knee joints of rats were experienced Safranin O‐fast green staining to evaluate the knee joint injury. FBXO3, pyroptosis‐associated proteins, and IL‐1β and IL‐18 expression in FLSs and articular cartilage tissues of rats were assessed by Western blot, qRT‐PCR and Enzyme‐linked immunosorbent assay. Results KOA cell model had higher apoptosis percentage, expression of pyroptosis‐associated proteins, and IL‐1β and IL‐18 level. miR‐219a‐5p up‐modulation decreased the above indicators, whereas miR‐219a‐5p down‐modulation increased the above indicators. FBXO3 expression was directly repressed by miR‐219a‐5p. Loss of FBXO3 suppressed the above indicators. FBXO3 counteracted the suppression of miR‐219a‐5p on the above indicators. miR‐219a‐5p agomir attenuated knee joint injury, increased step size of KOA rats, and reduced FBXO3, pyroptosis‐associated proteins and level of IL‐1β and IL‐18 in the articular cartilage tissues of KOA rats. Conclusion miR‐219a‐5p suppressed the pyroptosis in KOA by inactivating the NLRP3 signaling via targeting FBXO3, which might be a promising target for ameliorating KOA in the clinic.

Elucidating the role of ubiquitination and deubiquitination in osteoarthritis progression

“…FBXO3 counteracted the effects of miR-215a-5p-inhibited IL-18, IL-1b and pyroptosis-related proteins. Additionally, miR-219a-5p alleviated knee joint injury and elevated step size of rat with knee osteoarthritis partly via inhibition of FBXO3 and inactivation of NLRP3 (45).…”

“…This cell model exhibited elevation of IL-18, IL-1b, apoptosis rate, and increased expression of pyroptosis-associated proteins. The abovementioned indicators were downregulated by up-modulation of miR-219a-5p, while downregulation of miR-219a-5p exhibited the opposed results (45). FBXO3 expression was inhibited by miR-219a-5p, and depletion of FBXO3 repressed the expression of IL-18, IL-1b and pyroptosis-related proteins.…”

Pyroptosis-related crosstalk in osteoarthritis: Macrophages, fibroblast-like synoviocytes and chondrocytes

“…The down-regulation of miR-219a-5p was observed in FLS affected by OA. Further investigations revealed that miR-219a-5p has the potential to impede the progression of knee OA both in laboratory settings and living organisms by suppressing the expression of F-box protein 3 (FBXO3), thereby inhibiting pyroptosis [ 138 ]. Zhang and colleagues provide evidence that upregulation of HIF-1α in FLS and induction of pyroptosis may cause synovial fibrosis, while inhibition of HIF-1α or GSDMD may improve the marker of FLS fibrosis [ 13 ].…”

Effect of Duhuo Jisheng Decoction on miRNA-17-5p Expression and PI3K/Akt/mTOR/GSDMD Signaling Pathway in a Rat Model of Knee Osteoarthritis

“…Wang et al also found that miR-219a-5p inhibits pyroptosis in knee osteoarthritis via inactivating the NLRP3 signaling 20 . Chang et al comprehensively analyzed the key genes, signaling pathways and miRNAs of human knee osteoarthritis based on bioinformatics.…”