Decreased miR-214–3p activates NF-κB pathway and aggravates osteoarthritis progression

Abstract

Background: Osteoarthritis (OA), a disease with whole-joint damage and dysfunction, is the leading cause of disability worldwide. The progressive loss of hyaline cartilage extracellular matrix (ECM) is considered as its hallmark, but its exact pathogenesis needs to be further clarified. MicroRNA(miRNA) contributes to OA pathology and may help to identify novel biomarkers and therapies against OA. Here we identified miR-214À3p as an important regulator of OA. Methods: qRT-PCR and in situ hybridization were used to detect the expression level of miR-214À3p. The function of miR-214À3p in OA, as well as the interaction between miR-214À3p and its downstream mRNA target (IKBKB), was evaluated by western blotting, immunofluorescence, qRT-PCR and luciferase assay. Mice models were introduced to examine the function and mechanism of miR-214À3p in OA in vivo. Findings: In our study, we found that miR-214À3p, while being down-regulated in inflamed chondrocytes and OA cartilage, regulated ECM metabolism and cell apoptosis in the cartilage. Mechanically, the protective effect of miR-214À3p downregulated the IKK-b expression and led to the dysfunction of NF-kB signaling pathway. Furthermore, intra-articular injection of miR-214À3p antagomir in mice joints triggered spontaneous cartilage loss while miRNA-214À3p agomir alleviated OA in the experimental mouse models. Interpretation: Decreased miR-214À3p activates the NF-kB signaling pathway and aggravates OA development through targeting IKKb, suggesting miR-214À3p may be a novel therapeutic target for OA.

Anti‑inflammatory role of microRNA‑429 in human gingival epithelial cells‑inhibition of IL‑8 production through direct binding to IKKβ mRNA

“…Taken together, it was demonstrated that miR-429 suppressed IL-8 production, at least in part, through inhibiting NF-κB activation via direct binding to IKKβ. It has been reported that some miRNAs including miR-16, miR-148a, miR-199a, miR-497 and miR-200 negatively regulate IKKβ in a number of different types of cells (20,24,26,(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56). The present study provided the additional information that miR-429 is directly involved in the regulation of IKKβ in gingival epithelial cells.…”

“…This may be explained by the insufficient inhibition of miR-429 in the protocol for transient transfection. Another posibility is that the translation of IKKβ protein may be more complex and thus regulated by several other miRNAs as suggested in the previous studies (20,24,26,(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56). It could be that the inhibition of miR-429 alone may be insufficient to induce the upregulation of IKKβ protein (57).…”

miR-520c-3p regulates IL-1β-stimulated human chondrocyte apoptosis and cartilage degradation by targeting GAS2

“…For example, miR-144-3p ameliorates the progression of OA through blocking the MAPK, PI3K/Akt, and NF-κB signaling pathways. Another study conducted by Cao et al [ 18 ] found that decreased miR-214-3p activates NF-κB pathway and aggravates OA progression.…”

MiR-214-3p, a novel possible therapeutic target for the pathogenesis of osteoarthritis

“…The data obtained in vitro were further corroborated by in vivo results on animal model. Lastly, the study by Cao et al [8] showed that miR-214-3p significantly suppressed the activation of NF-kB pathway by targeting IKKb. These findings suggest a protective effect of miR-214-3p in cartilage metabolism and degradation, and the possible involvement of this miRNA in OA development and progression.…”

“…In a recent paper by Cao et al [8], published in EBioMedicine, it has been reported the data, obtained in human OA and mice primary chondrocyte cultures and in experimental animal model (adult male C57BL/6 mice), on the expression of miR-214-3p and on the possible implication of nuclear factor (NF)-kB pathway in miR-214-3p-mediated effects.…”