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Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
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USP8-mediated mitochondrial regulation in osteoclasts is essential for skeletal development
Sachin Chaugule1,2,3, Yeon-Suk Yang1,2,3, Tadatoshi Sato2,4,5
1Department of Genetic and Cellular Medicine, UMass Chan Medical School, Worcester, MA, USA.
Cellular and Molecular Life Sciences : CMLS
|January 15, 2026
Summary
Ubiquitin-specific protease 8 (USP8) is crucial for osteoclast function and skeletal development. Its absence impairs bone formation and growth by affecting mitochondria and cellular communication.
Area of Science:
- Skeletal Biology
- Cellular Regulation
- Biochemistry
Background:
- Aberrant protein regulation causes skeletal diseases.
- Deubiquitinating enzymes (DUBs) like USP8 regulate osteoclasts and osteoblasts.
Purpose of the Study:
- To investigate the role of USP8 in osteoclast development and its impact on skeletal formation.
- To elucidate the molecular mechanisms by which USP8 influences osteoclast function.
Main Methods:
- Genetic deletion of Usp8 in mouse osteoclasts (Usp8Ctsk).
- Analysis of bone mass, structure, and growth plate morphology.
- Assessment of mitochondrial function, mitophagy, ROS production, and inflammatory markers.
- Investigation of USP8's role in Parkin stabilization and mitophagy regulation.
Main Results:
- Usp8 deletion in osteoclasts impaired osteoclast development and bone resorption.
- Mice with Usp8-deficient osteoclasts exhibited low bone mass and short stature due to defective endochondral ossification.
- USP8 deficiency reduced mitochondrial activity and mitophagy, increasing ROS and inflammation.
- USP8 stabilizes Parkin to regulate mitophagy in osteoclasts.
- Usp8-deficient osteoclasts secreted factors that disrupted growth plate and bone formation.
Conclusions:
- USP8 is a critical regulator of osteoclast development and function.
- USP8 controls mitochondrial homeostasis and mitophagy in osteoclasts via Parkin stabilization.
- USP8-deficient osteoclasts alter the skeletal microenvironment, impacting bone and growth plate development.
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