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PPAR-γ Activation Alleviates Osteoarthritis through Both the Nrf2/NLRP3 and PGC-1α/Δψ m Pathways by Inhibiting

Zhencheng Feng1, Qiuxiang Huang2, Xingliang Zhang3,4

  • 1Department of Orthopedics, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 51022, China.

PPAR Research
|April 6, 2023
PubMed

Insights

Pioglitazone (Piog) activation of PPAR-gamma suppresses pyroptosis in osteoarthritis (OA) cartilage by enhancing Nrf2/NLRP3 and PGC1-alpha/Δψm pathways, offering a potential treatment for OA.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Rheumatology

Background:

  • Osteoarthritis (OA) is a prevalent degenerative joint disease with increasing incidence in aging and obese populations.
  • Emerging evidence suggests pyroptosis plays a role in OA pathogenesis, identifying it as a potential therapeutic target.
  • The precise relationship between peroxisome proliferator-activated receptor gamma (PPAR-γ) and NLRP3-mediated pyroptosis in OA cartilage remains unclear.

Purpose of the Study:

  • To investigate the role of PPAR-γ in regulating NLRP3-mediated pyroptosis in OA cartilage.
  • To elucidate the underlying molecular mechanisms connecting PPAR-γ activation to pyroptosis suppression in OA.
  • To evaluate the therapeutic potential of pioglitazone (Piog) in OA models.

Main Methods:

  • Analysis of NLRP3-mediated pyroptosis levels in human OA cartilage samples with varying severity.
  • In vitro studies using lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-induced primary chondrocytes.
  • In vivo studies utilizing knee OA rat models.
  • Pharmacological intervention with pioglitazone (Piog) and pathway inhibitors (Nrf2/NLRP3, PGC1-α/Δψm).

Main Results:

  • Higher levels of NLRP3-mediated pyroptosis were observed in severe OA cartilage compared to mild OA cartilage.
  • Pioglitazone (Piog) activation of PPAR-γ attenuated LPS/ATP-induced chondrocyte pyroptosis and arthritis in rat models.
  • The protective effects of Piog were partially reversed by inhibiting the Nrf2/NLRP3 or PGC-1α/Δψm pathways.
  • Complete abrogation of Piog's protective effects occurred when both pathways were simultaneously inhibited.

Conclusions:

  • Pioglitazone (Piog) protects OA cartilage from pyroptosis-induced damage by simultaneously activating the Nrf2/NLRP3 and PGC-1α/Δψm signaling pathways.
  • These activated pathways enhance antioxidative and anti-inflammatory responses and promote mitochondrial biogenesis.
  • Pioglitazone (Piog) shows promise as a potential therapeutic agent for human OA cartilage damage.

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