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Excessive inflammation and autophagy defect of chondrocytes play important roles in the pathological process of osteoarthritis (OA). The present study aimed to clarify the roles of small novel rich in cartilage (SNORC) in these pathological changes of chondrocytes in OA. Bioinformatics analysis of GEO dataset GSE207881 displayed that SNORC was a potential biomarker for OA. As confirmed by quantitative real-time PCR, immunohistochemical staining and western blotting, SNORC was significantly up-regulated in cartilage of OA rat model and interleukin (IL)-1β-stimulated primary rat articular chondrocytes in contrast to their corresponding normal control. Knocking down SNORC in IL-1β-induced chondrocytes obviously suppressed the production of nitric oxide (NO), IL-6, tumor necrosis factor (TNF)-α and prostaglandin E2 (PGE2) to alleviate inflammation, and reduced the protein levels of a disintegrin and metalloproteinase with thrombospondin 5 (ADAMTS5) and matrix metallopeptidase (MMP)13 and elevated collagen type 2 alpha 1 (COL2A1) level to improve matrix degradation. Down-regulation of SNORC increased Beclin1 expression and LC3II/LC3I ratio, but suppressed p62 expression to restore impaired autophagy in IL-1β-induced chondrocytes. Moreover, down-regulating SNORC mitigated mitochondrial dysfunction and apoptosis in IL-1β-stimulated chondrocytes. Mechanically, SNORC simultaneously activated the phosphatidylinositol-3-kinase/serine threonine kinase (PI3K/AKT) and c-Jun N-terminal kinase (JNK)/c-Jun signaling pathway in the IL-1β-induced chondrocyte, while re-activating the PI3K and JNK signals abolished the suppressive effect of down-regulating SNORC on IL-1β-induced chondrocyte damage. In a word, SNORC knockdown alleviates inflammation, matrix degradation, autophagy defect and excessive apoptosis of chondrocytes during OA development via suppressing the PI3K and JNK signaling pathway. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a common chronic joint degenerative disease and a major cause of disability in the elderly. However, the current intervention strategies cannot effectively improve OA, and the pathogenesis of OA remains elusive. The present study identified RNA binding motif protein 47 (RBM47) as an upstream modulator of key dysregulation gene co-expression module based on weighted gene co-expression network analysis (WGCNA) analysis and least absolute shrinkage and selection operator (Lasso) modeling. Subsequently, data from real-time quantitative PCR and western blot analysis revealed that RBM47 was upregulated in OA models in vivo and in vitro compared with normal controls. Functional analysis results from the MTT assay, flow cytometry, evaluation of LDH activities and inflammatory mediators, and western blot analysis of extracellular matrix (ECM) proteins, showed that RBM47 knockdown significantly alleviated inflammation, apoptosis, and ECM degradation in interleukin 1β (IL-1β)-treated chondrocytes. Mechanistically, RBM47 bound to F box only protein 2 (FBXO2) and stabilized FBXO2 messenger RNA (mRNA) to promote the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in chondrocytes. Results from the recovery assay showed that the re-activation of STAT3 signaling by overexpressing FBXO2 or STAT3 counteracted the alleviating effect of RBM47 downregulation on IL-1β-induced inflammation, apoptosis, and ECM degradation. Altogether, our findings illustrate that RBM47 stabilizes FBXO2 mRNA to advance OA development by activating STAT3 signaling, which enhances our understanding of the molecular regulatory mechanisms underlying the development of OA. [ABSTRACT FROM AUTHOR]