Work

USP8-mediated mitochondrial regulation in osteoclasts is essential for skeletal development

Year: 2026

Type: article

Abstract: Aberrant protein regulatory pathways disrupt bone development and contribute to skeletal diseases. The cysteine protease family of deubiquitinating enzymes (DUBs) are critical for regulation of bone-resorbing osteoclasts and bone-forming osteoblasts. Here, we demonstrate that the DUB ubiquitin-specific protease 8 (USP8) is highly expressed in osteoclasts and its deletion impairs osteoclast development and bone resorption activity. Deletion of Usp8 in osteoclasts ( Usp8 Ctsk ) results in low trabecular bone mass due to defective endochondral bone formation and short stature resulting from abnormal growth plate structure. Usp8 deficiency in osteoclasts reduces the number of mitochondrial, mitochondrial activity, oxidative phosphorylation, and mitophagy, while ROS production and inflammatory responses increased. USP8 mediates the regulation of mitophagy in osteoclasts through the stabilization of Parkin. Moreover, Usp8 -deficient osteoclasts in metaphysis secrete factors that impair both growth plate development and trabecular bone formation. Collectively, these findings identify USP8 as a key regulator of osteoclast development and secretory factor production, shaping the microenvironment essential for skeletal development.

Source: Cellular and Molecular Life Sciences

DOI: 10.1007/s00018-025-06012-0

Authors: Sachin Chaugule, Yeon-Suk Yang, Tadatoshi Sato, Emma Mayer, Jae-Hyuck Shim

Institutions: University of Massachusetts Chan Medical School, Harvard University, Massachusetts General Hospital

Language: English

Topic: Bone Metabolism and Diseases

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $4,290

Funder: National Institutes of Health