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HSC70 mediated autophagic degradation of oxidized PRL2 is responsible for osteoclastogenesis and inflammatory bone

Qi Li1, Tao Yue2, Xinyue Du1

  • 1Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

Cell Death and Differentiation
|October 1, 2022
PubMed

Insights

Prolin-2 (PRL2) regulates bone loss during inflammation. Reduced PRL2 accelerates osteoclast formation and bone destruction, suggesting PRL2 as a therapeutic target for inflammatory bone diseases.

Area of Science:

  • Molecular biology
  • Immunology
  • Bone biology

Background:

  • Inflammation causes bone loss through osteoporosis and local destruction.
  • Molecular mechanisms linking inflammation and bone destruction are not fully understood.
  • Osteoclastogenesis is a key process in bone resorption and inflammatory bone diseases.

Purpose of the Study:

  • To investigate the role of Prolin-2 (PRL2) in regulating osteoclastogenesis and bone resorption.
  • To elucidate the molecular mechanisms by which PRL2 influences bone metabolism during inflammation.
  • To evaluate PRL2 as a potential therapeutic target for inflammatory bone diseases.

Main Methods:

  • Utilized PRL2-deficient mice to assess bone phenotypes and osteoclast activity.
  • Investigated PRL2's interaction with RAC1 and reactive oxygen species (ROS) production.
  • Examined PRL2 degradation pathways mediated by HSC70 under oxidative stress.
  • Assessed the effects of PRL2 manipulation in mouse models of inflammatory bone disease and human rheumatoid arthritis samples.
  • Tested the efficacy of hydroxychloroquine, an autophagy inhibitor, in blocking inflammation-induced bone destruction.

Main Results:

  • PRL2 deficiency led to decreased bone volume and increased osteoclast numbers.
  • PRL2 negatively regulates RANKL-induced ROS production via RAC1 activation.
  • Oxidative stress triggers PRL2 degradation through HSC70-mediated autophagy.
  • PRL2 ablation exacerbated bone damage in inflammatory bone disease models.
  • Reduced PRL2 levels correlated with bone destruction in mouse arthritis and human rheumatoid arthritis.
  • Hydroxychloroquine treatment ameliorated inflammation-induced bone destruction in vivo.

Conclusions:

  • PRL2 is identified as a novel negative regulator of osteoclastogenesis and bone resorption.
  • PRL2 acts as a crucial link between inflammation and osteoporosis, influencing osteoimmunity.
  • Targeting PRL2 or inhibiting its autophagic degradation by HSC70 presents a potential therapeutic strategy for inflammatory bone diseases.

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