SOX4-activated lncRNA MCM3AP-AS1 aggravates osteoarthritis progression by modulating miR-149-5p/Notch1 signaling

Cytokine. 2022 Apr:152:155805. doi: 10.1016/j.cyto.2022.155805. Epub 2022 Feb 21.

Abstract

Objective: To clarify the expression and underlying network of long non-coding RNA (lncRNA) MCM3AP-AS1 in osteoarthritis (OA).

Methods: Human articular cartilage samples, OA model rats and IL-1β-treated C28/I2 cells were used in this study. The expression changes of genes and proteins were assessed by real-time quantitative PCR (qRT-PCR) and western blot. Cell viability, apoptosis, autophagy and extracellular matrix (ECM) degradation were assessed by Cell Counting Kit-8 (CCK-8), immunohistochemistry (IHC), flow cytometry, immunofluorescence and western blot assays, respectively. Molecule interactions were validated by dual luciferase and Chromatin immunoprecipitation (ChIP) assays. H&E staining was used to detect the pathological changes of cartilage.

Results: MCM3AP-AS1 was upregulated in OA patients and IL-1β-induced chondrocytes. Knockdown of MCM3AP-AS1 enhanced autophagy, while alleviated ECM degradation and cartilage injury. Mechanistically, overexpression of SOX4 boosted the transcription of MCM3AP-AS1. Moreover, MCM3AP-AS1 functioned as a molecular sponge or epigenetic regulator of miR-149-5p to facilitate Notch1 expression. Functional rescue experiments showed that either inhibition of miR-149-5p nor ectopic expression of Notch1 dramatically weakened the biological impacts of MCM3AP-AS1 silencing.

Conclusion: These finding demonstrated that SOX4-activated MCM3AP-AS1 aggravated OA progression by modulating autophagy and ECM degradation via targeting miR-149-5p/Notch1 axis. These data supported that inhibition of MCM3AP-AS1 might be a potential treatment strategy of OA.

Keywords: Autophagy; MCM3AP-AS1; Notch1; Osteoarthritis; SOX4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / genetics
  • Acetyltransferases / metabolism
  • Animals
  • Apoptosis / physiology
  • Cell Proliferation
  • Chondrocytes / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Osteoarthritis* / genetics
  • Osteoarthritis* / metabolism
  • RNA, Long Noncoding* / genetics
  • RNA, Long Noncoding* / metabolism
  • Rats
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • SOXC Transcription Factors / metabolism
  • Signal Transduction

Substances

  • Intracellular Signaling Peptides and Proteins
  • MIRN149 microRNA, human
  • MicroRNAs
  • NOTCH1 protein, human
  • Notch1 protein, rat
  • RNA, Long Noncoding
  • Receptor, Notch1
  • SOX4 protein, human
  • SOXC Transcription Factors
  • Acetyltransferases
  • MCM3AP protein, human