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NRF2 Is an Upstream Regulator of MYC-Mediated Osteoclastogenesis and Pathological Bone Erosion

Peter Sang Uk Park1, Se Hwan Mun1, Steven L Zeng1

  • 1Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA.

Cells
|September 24, 2020
PubMed

Insights

Nuclear factor erythroid 2-related factor 2 (NRF2) negatively regulates osteoclast formation by suppressing MYC. Targeting this NRF2-MYC pathway offers new therapeutic strategies for bone diseases like inflammatory arthritis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Osteoclasts are critical for bone remodeling and pathological bone destruction.
  • Targeting osteoclasts is a therapeutic strategy for bone diseases, but requires improved specificity and reduced side effects.
  • MYC is crucial for osteoclast differentiation, but its upstream regulators are not fully understood.

Purpose of the Study:

  • To identify novel upstream regulators of MYC in osteoclast differentiation.
  • To investigate the role of nuclear factor erythroid 2-related factor 2 (NRF2) in regulating osteoclastogenesis.
  • To explore the therapeutic potential of the NRF2-MYC axis in bone diseases.

Main Methods:

  • Investigated NRF2 as an upstream regulator of MYC in osteoclast differentiation.
  • Utilized in vivo and in vitro models of osteoclastogenesis and inflammatory arthritis.
  • Analyzed the effects of NRF2 deficiency and MYC ablation on osteoclast activity and bone loss.

Main Results:

  • Identified NRF2 as a novel negative regulator of MYC transcription in osteoclasts.
  • NRF2 suppresses receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis via ERK and p38 signaling pathways.
  • Ablation of MYC reversed enhanced osteoclastogenesis in NRF2-deficient models and protected against pathological bone loss.

Conclusions:

  • The novel NRF2-MYC axis fine-tunes osteoclast formation.
  • This pathway presents a new therapeutic target for preventing pathological bone erosion in diseases like inflammatory arthritis.
Keywords:
MYCNRF2RANKL signalingosteoclasts

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