Overexpression of microRNA-1 controls the development of osteoarthritis via targeting FZD7 of Wnt/β-catenin signaling

Abstract

Purpose: MiRNA-381 is known to regulate osteoarthritic cartilage degeneration in our previous study, but its target remains unclear. The aim of this study is to identify histone deacetylase 4 (HDAC4), an inhibitor of chondrocyte hypertrophy, as a target of miRNA-381. Methods: The long bone of forearm in mouse embryo served as an in vivo model of chondrogenesis and hypertrophy. The expression of miRNA-381was determined by in situ hybridization, while HDAC4 and MMP13 levels were detected by immunohistochemistry.SW1353 chondrocyte-like cells and primary mouse chondrocytes (PMCs) was transfected with miRNA-381 mimic or miRNA-381 inhibitor in vitro. HDAC4 siRNA was used to determine its function in chondrocyte differentiation and hypertrophy. Direct interaction between miR-381 and putative site in the 3 0-untranslated region (3 0-UTR) of HDAC4 messenger RNA was validated by luciferase reporter assay. Results: MiRNA-381, RUNX2 and MMP13 were mainly expressed in hypertrophic chondrocytes, while HDAC4 showed a high expression in pre-hypertrophicchondrocytes and decreased apparently in hypertrophic zone. Overexpression of miRNA-381 suppressed the activity of a reporter construct containing the 3 0-UTR, decreased HDAC4 expression and increased acetylated-Histone H3, RUNX2 and MMP13. Down-regulaiton of HDAC4 using siRNA significantly increased RUNX2 expression. Conclusions: MiRNA381 epigenetically regulates chondrocyte hypertrophy and degeneration by directly targeting HDAC4.

Identification and verification of a novel signature that combines cuproptosis-related genes with ferroptosis-related genes in osteoarthritis using bioinformatics analysis and experimental validation

“…ssGSEA showed that CDKN1A significantly positively correlated with TNF-α signaling via NF-κB, the TGF-β signaling pathway, hypoxia, the P53 pathway, apoptosis, mTORC1 signaling, and other gene sets, suggesting that CDKN1A may affect OA by regulating inflammation, apoptosis, and hypoxia. Although both the CDKN1A and GABARAPL2 genes have been reported previously [ 49 – 52 ], their relationship with ferroptosis and cuproptosis in OA is not yet known. This suggests that these genes may be targets not only for immunotherapy, inflammation, and autophagy but also for the treatment of cuproptosis and ferroptosis in OA.…”