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Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
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Phosphorylation-dependent osterix degradation negatively regulates osteoblast differentiation.

Seira Hoshikawa1,2, Kouhei Shimizu2, Asami Watahiki2

  • 1Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai, Japan.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|September 15, 2020
PubMed
Summary

Proteasome inhibitors stabilize osterix/Sp7 (Osx) protein, promoting bone formation. Targeting the Osx degradation pathway enhances osteogenesis and bone regeneration.

Keywords:
Fbw7p38ubiquitination

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Proteasome inhibitors promote bone formation by increasing osteoblast markers.
  • The precise molecular mechanisms regulating osteogenic factors via proteasomal degradation remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms controlling osterix/Sp7 (Osx) protein stability.
  • To investigate the role of p38 and Fbw7 in Osx proteasomal degradation.
  • To explore the therapeutic potential of targeting the Osx degradation pathway for bone regeneration.

Main Methods:

  • Utilized proteasome inhibitors (bortezomib, ixazomib) to assess effects on Osx protein levels.
  • Investigated Osx phosphorylation, ubiquitination, and interaction with p38 and Fbw7.
  • Employed p38 knockdown and pharmacological inhibition, along with Fbw7 depletion in cell models.

Main Results:

  • Proteasome inhibitors significantly increased Osx protein levels.
  • p38-mediated phosphorylation of Osx at S73/77 facilitates Fbw7 binding and subsequent ubiquitination.
  • p38 inhibition stabilized Osx, enhancing osteoblast differentiation; however, prior inhibition impaired osteogenesis, indicating dual roles for p38.
  • Fbw7 depletion in mesenchymal stem cells and calvarial cells boosted osteogenic capacity.

Conclusions:

  • Uncovered the p38 and Fbw7-mediated proteasomal degradation pathway controlling Osx stability.
  • Demonstrated that modulating Osx degradation offers a potential strategy for enhancing osteogenesis and bone matrix regeneration.