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REGγ is essential to maintain bone homeostasis by degrading TRAF6, preventing osteoporosis

Yingying Du1, Hui Chen2,3,4, Lei Zhou5

  • 1Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.

Proceedings of the National Academy of Sciences of the United States of America
|November 13, 2024
PubMed

Insights

Researchers identified REGγ as a biomarker for osteoporosis. REGγ deficiency worsens bone loss, while its inhibition of TRAF6 protects bone, suggesting TTP22 as a potential osteoporosis treatment.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Endocrinology

Background:

  • Osteoporosis is a silent disease characterized by low bone mass and fragility.
  • Urgent need for novel biomarkers and therapeutic strategies for osteoporosis.
  • REGγ's role in bone metabolism was previously unknown.

Purpose of the Study:

  • Identify REGγ as a potential biomarker for osteoporosis.
  • Elucidate the mechanism of REGγ in regulating bone metabolism.
  • Investigate TTP22 as a potential therapeutic agent for osteoporosis.

Main Methods:

  • Proteomics analysis to identify REGγ.
  • Generation and analysis of REGγ knockout and overexpression mouse models.
  • Investigation of the REGγ-20S proteasome-TRAF6 degradation pathway.
  • In vitro and in vivo studies using TTP22, a CKII inhibitor.

Main Results:

  • REGγ deficiency led to increased osteoclast activity and bone loss.
  • REGγ-20S proteasome ubiquitin-independently degrades TRAF6, inhibiting bone resorption.
  • Overexpression of REGγ reduced osteoclast activity.
  • TTP22 treatment alleviated osteoporosis in vitro and in vivo.

Conclusions:

  • The NIP30/REGγ/TRAF6 axis plays a critical role in osteoporosis pathogenesis.
  • REGγ acts as a negative regulator of osteoclastogenesis by degrading TRAF6.
  • TTP22 demonstrates therapeutic potential for treating osteoporosis.
Keywords:
NIP30REGγTRAF6osteoporosisubiquitin-independent degradation

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