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DDIT3/CHOP promotes LPS/ATP-induced pyroptosis in osteoblasts via mitophagy inhibition

Zhipeng Dong1, Beining Yang1, Meie Jia1

  • 1The State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, China.

Biochimica Et Biophysica Acta. Molecular Cell Research
|March 23, 2024
PubMed

Insights

Inflammation induces osteoblast pyroptosis via endoplasmic reticulum stress. DNA damage-inducible transcript 3 (DDIT3)/CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) promotes this by inhibiting mitophagy.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Immunology

Background:

  • Inflammatory environments can induce endoplasmic reticulum (ER) stress, leading to pyroptosis in various cell types.
  • DNA damage-inducible transcript 3 (DDIT3)/CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is a key ER stress factor upregulated in osteoblasts during inflammation.
  • The role of DDIT3/CHOP in regulating osteoblast pyroptosis under inflammatory conditions requires further investigation.

Purpose of the Study:

  • To investigate the role of DDIT3/CHOP in lipopolysaccharides (LPS)/adenosine 5'-triphosphate (ATP)-induced osteoblast pyroptosis.
  • To elucidate the underlying mechanism involving PTEN-induced kinase 1 (PINK1)/E3 ubiquitin-protein ligase parkin (Parkin)-mediated mitophagy.

Main Methods:

  • Osteoblast cell culture and stimulation with LPS/ATP.
  • Overexpression of DDIT3/CHOP.
  • Assessment of pyroptosis markers (NLRP3, caspase-1, GSDMD).
  • Analysis of mitophagy using fluorescence imaging and Western blot.
  • Pharmacological manipulation of mitophagy with carbonyl cyanide 3-chlorophenylhydrazone (CCCP).

Main Results:

  • LPS/ATP stimulation induced osteoblast pyroptosis and increased DDIT3/CHOP expression.
  • DDIT3/CHOP overexpression exacerbated pyroptosis, evidenced by increased inflammasome activation and pyroptosis executioner levels.
  • LPS/ATP stimulation promoted PINK1/Parkin-mediated mitophagy, which was suppressed by DDIT3/CHOP overexpression.
  • Inhibition of mitophagy by DDIT3/CHOP overexpression led to increased pyroptosis.
  • CCCP treatment reversed the effect of DDIT3/CHOP on pyroptosis.

Conclusions:

  • DDIT3/CHOP promotes osteoblast pyroptosis in inflammatory environments.
  • This promotion occurs through the inhibition of PINK1/Parkin-mediated mitophagy.
  • DDIT3/CHOP is a key regulator linking ER stress to pyroptosis in osteoblasts via mitophagy pathways.
Keywords:
DDIT3/CHOPMitophagyOsteoblastPyroptosis

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