Activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) induces cell death through MAPK-dependent

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Sung Hun Kim1, Chong Il Yoo, Hui Taek Kim

  • 1Department of Orthopedic Surgery, College of Medicine, Pusan National University, Pusan, Korea.

Toxicology and Applied Pharmacology
|April 18, 2006
PubMed

Insights

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists like ciglitazone induce osteoblast cell death via apoptosis. Mitogen-activated protein kinase (MAPK) pathways, including ERK and p38, mediate this process, involving reactive oxygen species and mitochondrial dysfunction.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Pharmacology

Background:

  • Osteoblastic cells are crucial for bone health.
  • PPARγ agonists are used in treating metabolic disorders.
  • Understanding their effects on osteoblasts is vital for osteoporosis therapy.

Purpose of the Study:

  • To investigate the role of MAPK subfamilies in PPARγ agonist-induced osteoblastic cell death.
  • To elucidate the signaling pathways involved in ciglitazone-induced apoptosis.

Main Methods:

  • Osteoblastic cells were treated with PPARγ agonists (ciglitazone, troglitazone) and a PPARα agonist (ciprofibrate).
  • Reactive oxygen species (ROS) generation, apoptosis markers (Bax, caspase activation), mitochondrial membrane potential, and MAPK activation (ERK, p38) were assessed.
  • Inhibitors of PPARγ, ROS, MAPK pathways, and EGFR were used to determine mechanisms.

Main Results:

  • PPARγ agonists induced concentration- and time-dependent apoptosis in osteoblasts, while PPARα agonists had no effect.
  • Ciglitazone-induced cell death involved ROS generation, Bax upregulation, mitochondrial dysfunction, and caspase activation.
  • MAPK pathways (ERK, p38), activated by ciglitazone, were essential for cell death, functioning upstream of mitochondrial events.
  • EGFR signaling was upstream of ERK activation.

Conclusions:

  • MAPK signaling pathways are critical mediators of PPARγ agonist-induced osteoblastic cell death.
  • The mechanism involves ROS generation and mitochondrial-dependent apoptosis.
  • These findings offer insights into potential therapeutic strategies for osteoporosis.

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