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Construction and Evaluation of a Murine Calvarial Osteolysis Model by Exposure to CoCrMo Particles in Aseptic Loosening
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NRF2 is a critical regulator and therapeutic target of metal implant particle-incurred bone damage

Jian Dong1, Lijun Zhang2, Binjia Ruan3

  • 1State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Branch of National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School. 321 Zhongshan Road, Nanjing 210008, China.

Biomaterials
|August 27, 2022
PubMed

Insights

Metal wear particles cause bone damage and implant loosening by suppressing NRF2. Restoring NRF2 with TBHQ protects against osteolysis, offering a potential therapeutic strategy for joint replacement complications.

Area of Science:

  • Biomedical Engineering
  • Orthopedics
  • Cell Biology

Background:

  • Aseptic loosening of artificial joints is a significant complication of total joint arthroplasty.
  • Wear particles from implants induce osteolysis, leading to implant failure and revision surgery.
  • The molecular mechanisms regulating wear particle-induced bone damage remain incompletely understood.

Purpose of the Study:

  • To investigate the role of Nuclear factor erythroid derived 2-related factor 2 (NRF2) in metal wear particle-induced osteolysis.
  • To evaluate the therapeutic potential of NRF2 activation in mitigating bone damage associated with joint implants.

Main Methods:

  • Utilized a mouse model of calvarial osteolysis induced by titanium particles (TiPs) and cobalt-chromium-molybdenum particles.
  • Assessed osteolysis severity in wild-type and Nfe2l2 knockout mice.
  • Administered the NRF2 agonist tert-butylhydroquinone (TBHQ) to evaluate its protective effects.
  • Examined the impact of TiPs and TBHQ on osteoblastogenesis and osteoclastogenesis in vitro.

Main Results:

  • TiPs induced severe osteolysis and suppressed NRF2 expression in mice.
  • Nfe2l2 knockout mice exhibited exacerbated osteolytic lesions after TiP exposure.
  • TBHQ treatment significantly alleviated osteolysis and normalized the expression of NRF2-dependent genes.
  • TBHQ effectively inhibited TiP-induced adverse effects on bone cell differentiation in a manner dependent on NRF2.

Conclusions:

  • NRF2 suppression is a key factor in the pathogenesis of osteolysis caused by metal wear particles.
  • Activating NRF2 represents a promising therapeutic strategy to reduce bone damage and potentially prevent aseptic implant loosening.
Keywords:
Bone damageMetal particleNRF2Oxidative stressTBHQ

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