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Glucocorticoids induce apoptosis and matrix metalloproteinase-13 expression in chondrocytes through the NOX4/ROS/p38

Ying Huang1, Gui-Quan Cai2, Jian-Ping Peng2

  • 1Department of Anesthesiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 200092, Shanghai, China.

The Journal of Steroid Biochemistry and Molecular Biology
|March 13, 2018
PubMed

Insights

Dexamethasone (Dex) increases cell death by raising reactive oxygen species (ROS) via NOX4. Inhibiting NOX4, ROS, or p38 MAPK protects chondrocytes from Dex-induced apoptosis and matrix breakdown.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Pharmacology

Background:

  • Dexamethasone (Dex) is known to induce chondrocyte apoptosis and matrix catabolism.
  • The precise mechanism by which Dex increases reactive oxygen species (ROS) and causes these effects remains unclear.
  • Nicotinamide adenine dinucleotide (phosphate) (NADPH) oxidase 4 (NOX4) is a key enzyme in ROS production during inflammation.

Purpose of the Study:

  • To investigate the role of NOX4 in dexamethasone-induced ROS overproduction in chondrocytes.
  • To elucidate the signaling pathway involved in Dex-induced chondrocyte apoptosis and matrix metalloproteinase 13 (MMP-13) expression.

Main Methods:

  • Healthy human chondrocytes were treated with Dex.
  • NOX4 and p38 mitogen-activated protein kinase (MAPK) expression levels were assessed.
  • Chondrocytes were treated with NOX inhibitors (apocynin), ROS scavengers, and p38 MAPK inhibitors.
  • Apoptosis, cell viability, and MMP-13 expression were evaluated.
  • NOX4 was silenced using specific techniques.

Main Results:

  • Dex treatment increased NOX4 expression through the glucocorticoid receptor (GR).
  • NOX inhibition and ROS scavenging reduced intracellular ROS and p38 MAPK activation.
  • Inhibiting NOX4, ROS, or p38 MAPK protected chondrocytes from Dex-induced apoptosis.
  • These treatments also blocked MMP-13 expression, and NOX4 silencing similarly reduced MMP-13 and p38 MAPK levels.

Conclusions:

  • Dexamethasone triggers chondrocyte apoptosis and MMP-13 expression via the NOX4/ROS/p38 MAPK signaling pathway.
  • NOX4 is identified as a potential therapeutic target for mitigating Dex-induced chondrocyte damage.
Keywords:
ApoptosisMMP-13NADPH oxidase 4p38 MAPK

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