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RARRES2 deficiency inhibits postmenopausal osteoporosis by promoting ferroptosis-mediated osteoclast differentiation

Yifan Wang1, Jiabin Lin1, Xinyao Cui1

  • 1Department of Bone and Soft Tissue Repair and Reconstructive Surgery, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China.

Connective Tissue Research
|August 3, 2026
PubMed
Abstract

Insights

Retinoic acid receptor responder 2 (RARRES2) knockdown inhibits osteoclast differentiation and progression of postmenopausal osteoporosis (PMOP). This occurs by suppressing Nrf2/GPX4 activation and promoting osteoclast ferroptosis.

Area of Science:

  • Bone Biology
  • Cellular Mechanisms
  • Osteoporosis Research

Background:

  • Postmenopausal osteoporosis (PMOP) is characterized by increased osteoclast activity.
  • Retinoic acid receptor responder 2 (RARRES2) role in PMOP is not fully understood.
  • Investigating RARRES2's impact on osteoclast differentiation is crucial for PMOP treatment.

Purpose of the Study:

  • To investigate the effects of RARRES2 on osteoclast differentiation in PMOP.
  • To elucidate the underlying mechanisms of RARRES2's action.
  • To explore potential therapeutic targets for PMOP.

Main Methods:

  • Established a rat model of PMOP using bilateral ovariectomy (OVX).
  • Induced in vitro osteoclast differentiation using RAW264.7 cells treated with RANKL and M-CSF.
  • Analyzed bone structure, biomechanics, histology, gene expression, Fe2+ levels, ROS, and lipid peroxidation.

Main Results:

  • OVX rats showed significant bone loss, increased osteoclasts, and upregulated RARRES2 expression.
  • RARRES2 knockdown suppressed osteoclast differentiation and TRAP activity in vitro.
  • RARRES2 knockdown promoted osteoclast ferroptosis by altering Nrf2/GPX4 pathway and increasing Fe2+, ROS, and lipid peroxidation.

Conclusions:

  • RARRES2 knockdown inhibits osteoclast differentiation and alleviates PMOP progression.
  • The mechanism involves suppressing Nrf2/GPX4 activation and promoting osteoclast ferroptosis.
  • Targeting RARRES2 may offer a novel therapeutic strategy for PMOP.
Keywords:
Postmenopausal osteoporosisRARRES2ferroptosislipid peroxidationosteoclast differentiation

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