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A clinical-stage Nrf2 activator suppresses osteoclast differentiation via the iron-ornithine axis

Yimin Dong1, Honglei Kang1, Renpeng Peng1

  • 1Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Cell Metabolism
|April 3, 2024
PubMed

Insights

Bitopertin, a novel Nrf2 activator, treats osteoporosis by inhibiting osteoclast differentiation and bone loss. This glycine uptake inhibitor shows fewer side effects than existing treatments, revealing a new Nrf2-iron-ornithine pathway.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Activating Nrf2 (Nuclear factor erythroid 2-related factor 2) is a therapeutic strategy for postmenopausal osteoporosis.
  • The precise mechanisms by which Nrf2 regulates osteoclast differentiation are not fully understood.
  • There are no approved Nrf2 activators for chronic disease treatment.

Purpose of the Study:

  • To investigate the potential of bitopertin, a glycine uptake inhibitor, as an Nrf2 activator for treating osteoporosis.
  • To elucidate the molecular mechanisms underlying Nrf2's role in osteoclast differentiation.
  • To identify novel therapeutic targets and pathways for osteoporosis treatment.

Main Methods:

  • In vitro studies on osteoclast differentiation.
  • In vivo studies using an ovariectomy-induced osteoporosis mouse model.
  • Analysis of Keap1-Nrf2 interaction, protein ubiquitination, and degradation.
  • Gene expression analysis of Slc40a1 and Odc1.
  • Assessment of intracellular iron and ornithine levels in osteoclasts.

Main Results:

  • Bitopertin activates Nrf2 by inhibiting Keap1-Nrf2 binding, reducing Nrf2 degradation, and suppressing osteoclast differentiation.
  • Bitopertin ameliorates ovariectomy-induced bone loss in mice.
  • Bitopertin demonstrates a favorable safety profile compared to existing Nrf2 activators in mice and humans.
  • Nrf2 upregulates Slc40a1, decreasing intracellular iron in osteoclasts.
  • Reduced Nrf2 or iron supplementation increases Odc1, lowering ornithine and promoting osteoclast differentiation.

Conclusions:

  • Bitopertin is a novel, clinical-stage Nrf2 activator that effectively treats osteoporosis.
  • A new Nrf2-regulated metabolic axis involving iron and ornithine in osteoclasts has been identified.
  • Bitopertin represents a promising therapeutic candidate for postmenopausal osteoporosis with a potentially improved safety profile.
Keywords:
NRF2Odc1Slc40a1bitopertinironornithineosteoclastosteoporosis

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