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Deubiquitinating Enzyme USP8 Is Essential for Skeletogenesis by Regulating Wnt Signaling

Sachin Chaugule1, Jung-Min Kim1, Yeon-Suk Yang1

  • 1Shim Lab, Division of Rheumatology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.

International Journal of Molecular Sciences
|October 13, 2021
PubMed

Insights

The deubiquitinating enzyme ubiquitin-specific protease 8 (USP8) is vital for bone development. USP8 stabilizes a key Wnt receptor, ensuring proper osteoblast differentiation and skeletal mineralization.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Developmental Biology

Background:

  • Skeletal stem cell differentiation is critical for skeletogenesis.
  • Ubiquitin-mediated protein degradation regulates stemness and osteogenic potential.
  • Deubiquitinating enzymes (DUBs) play a role in cellular processes.

Purpose of the Study:

  • To investigate the role of ubiquitin-specific protease 8 (USP8) in osteoprogenitor differentiation.
  • To elucidate the mechanism by which USP8 influences Wnt/β-catenin signaling.
  • To determine USP8's contribution to skeletal development and mineralization.

Main Methods:

  • Utilized knockout mouse models with deletion of USP8 in osteoprogenitors.
  • Examined the stabilization of Wnt receptor frizzled 5 (FZD5) by USP8.
  • Assessed Wnt/β-catenin signaling activity and skeletal mineralization.
  • Performed transplantation assays with USP8-deficient osteoprogenitors.

Main Results:

  • USP8 stabilizes frizzled 5 (FZD5) by inhibiting its lysosomal degradation.
  • USP8 is essential for Wnt/β-catenin signaling in osteoprogenitors.
  • Deletion of USP8 leads to a severe blockade in skeletal mineralization.
  • USP8-deficient osteoprogenitors failed to induce bone formation upon transplantation.

Conclusions:

  • The deubiquitinating enzyme USP8 is crucial for Wnt/β-catenin signaling in osteoprogenitors.
  • USP8 plays an essential role in osteogenesis and skeletal development.
  • Targeting USP8 may offer therapeutic strategies for bone-related disorders.
Keywords:
FZD5USP8Wnt signalingdeubiquitinating enzymeosteoblastskeletogenesis

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