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Peroxiredoxin 1-Toll-like receptor 4-p65 axis inhibits receptor activator of nuclear factor kappa-B ligand-mediated

Jisu Park1, Sanggil Kim2, Hye-Yeon Jung3

  • 1Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.

Iscience
|December 25, 2024
PubMed

Insights

Peroxiredoxin 1 (PRDX1) suppresses bone-resorbing osteoclast formation by regulating Toll-like receptor 4 (TLR4) signaling. This antioxidant enzyme redirects transcription factors to inhibit osteoclastogenesis, offering therapeutic potential for bone diseases.

Area of Science:

  • Biochemistry
  • Immunology
  • Cell Biology

Background:

  • Peroxiredoxin 1 (PRDX1) is an antioxidant enzyme involved in inflammation.
  • Its role in osteoclast differentiation via Toll-like receptor 4 (TLR4) signaling is not well understood.

Purpose of the Study:

  • To elucidate the mechanism of the PRDX1-TLR4 axis in regulating osteoclast differentiation.
  • To investigate the therapeutic potential of PRDX1 in bone disorders.

Main Methods:

  • Pharmacological inhibition of PRDX1 and TLR4 pathways.
  • Transcriptome analysis to identify PRDX1-regulated genes.
  • Western blotting and chromatin immunoprecipitation assays to study protein-DNA interactions.
  • Structural analysis of PRDX1 mutants.

Main Results:

  • PRDX1 suppresses RANKL-induced osteoclast differentiation through TLR4/TRIF and TLR4/MyD88 pathways.
  • PRDX1 upregulates serum amyloid A3 (Saa3) and aconitate decarboxylase 1 (Acod1) expression.
  • PRDX1 redirects p65 binding from Nfatc1 to Saa3 and Acod1 promoters, inhibiting osteoclastogenesis.
  • A PRDX1 mutant with enhanced TLR4 binding showed potent inhibition of osteoclast differentiation.

Conclusions:

  • The PRDX1-TLR4 axis is a novel regulator of osteoclast differentiation.
  • PRDX1's ability to modulate transcription factor binding offers therapeutic strategies for bone diseases.
Keywords:
Cellular physiologyMolecular biologyTranscriptomics

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