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MicroRNA-455-3p promotes TGF-β signaling and inhibits osteoarthritis development by directly targeting PAK2

Shu Hu1, Xiaoyi Zhao1, Guping Mao1

  • 1Department of Joint Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.

Experimental & Molecular Medicine
|October 6, 2019
PubMed

Insights

MicroRNAs (miRNAs) regulate osteoarthritis (OA) by targeting P21-activated kinase 2 (PAK2). Suppressing PAK2 inhibits cartilage degeneration, suggesting miR-455-3p and PAK2 as potential OA therapeutics.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cell Biology

Background:

  • MicroRNAs (miRNAs) are implicated in osteoarthritis (OA) pathogenesis.
  • P21-activated kinases (PAKs) role in OA remains understudied.
  • Investigating miR-455-3p's regulation of cartilage degeneration via PAK2.

Purpose of the Study:

  • Determine if miR-455-3p targets PAK2 to influence OA.
  • Elucidate the molecular mechanisms of miR-455-3p in chondrogenesis and OA.
  • Evaluate therapeutic potential of miR-455-3p and PAK2 in OA.

Main Methods:

  • Utilized miR-455-3p knockout mice to assess cartilage integrity.
  • Analyzed miR-455-3p and PAK2 expression in human adipose-derived stem cell (hADSC) chondrogenesis and OA chondrocytes.
  • Performed luciferase reporter assays to confirm direct targeting of PAK2 mRNA 3'-UTRs by miR-455-3p.
  • Investigated effects of PAK inhibition (IPA-3) and PAK2 suppression on chondrocyte gene expression and TGF-β/Smad signaling.

Main Results:

  • miR-455-3p knockout mice exhibited significant knee cartilage degeneration.
  • miR-455-3p expression was upregulated, while PAK2 expression was downregulated in late-stage hADSC chondrogenesis and OA chondrocytes.
  • Overexpression of miR-455-3p or suppression of PAK2 upregulated cartilage-specific genes and downregulated hypertrophy-related genes.
  • miR-455-3p directly targets PAK2 mRNA.
  • PAK inhibition and PAK2 suppression promoted R-Smad activation in the TGF-β/Smad pathway.
  • IPA-3 treatment ameliorated OA-induced cartilage degeneration.

Conclusions:

  • miR-455-3p inhibits cartilage degeneration in OA by directly suppressing PAK2.
  • This regulation involves the promotion of TGF-β/Smad signaling in chondrocytes.
  • miR-455-3p represents a potential therapeutic agent, while PAK2 is a potential therapeutic target for OA treatment.

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