Deubiquitinating Enzyme USP8 Is Essential for Skeletogenesis by Regulating Wnt Signaling

Int J Mol Sci. 2021 Sep 24;22(19):10289. doi: 10.3390/ijms221910289.


Disturbance in a differentiation program of skeletal stem cells leads to indecorous skeletogenesis. Growing evidence suggests that a fine-tuning of ubiquitin-mediated protein degradation is crucial for skeletal stem cells to maintain their stemness and osteogenic potential. Here, we demonstrate that the deubiquitinating enzyme (DUB) ubiquitin-specific protease 8 (USP8) stabilizes the Wnt receptor frizzled 5 (FZD5) by preventing its lysosomal degradation. This pathway is essential for Wnt/β-catenin signaling and the differentiation of osteoprogenitors to mature osteoblasts. Accordingly, deletion of USP8 in osteoprogenitors (Usp8Osx) resulted in a near-complete blockade in skeletal mineralization, similar to that seen in mice with defective Wnt/β-catenin signaling. Likewise, transplanting USP8-deficient osteoprogenitors under the renal capsule in wild-type secondary hosts did not to induce bone formation. Collectively, this study unveils an essential role for the DUB USP8 in Wnt/β-catenin signaling in osteoprogenitors and osteogenesis during skeletal development.

Keywords: FZD5; USP8; Wnt signaling; deubiquitinating enzyme; osteoblast; skeletogenesis.

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Endopeptidases / metabolism*
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Osteoblasts / metabolism
  • Osteoblasts / physiology
  • Osteogenesis / physiology*
  • Stem Cells / metabolism
  • Stem Cells / physiology
  • Ubiquitin Thiolesterase / metabolism*
  • Wnt Signaling Pathway / physiology*
  • beta Catenin / metabolism


  • Endosomal Sorting Complexes Required for Transport
  • beta Catenin
  • Endopeptidases
  • Ubiquitin Thiolesterase
  • Usp8 protein, mouse