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

Aberrant protein regulatory pathways disrupt bone homeostasis and contribute to skeletal diseases. Many of 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 (Usp8Ctsk) results in low bone mass due to defective endochondral ossification and short stature resulting from abnormal growth plate structure. Mechanistically, USP8 deficiency in osteoclasts dampens mitochondrial number, activity, oxidative phosphorylation, and mitophagy, while reactive oxygen species (ROS) inflammatory responses are increased in these cells. Moreover, USP8-deficient osteoclasts in metaphysis produce secretory factors that hinder both cartilage formation in the growth plate 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.