USP7 deletion promotes osteoclastogenesis via stimulating NF-κB and attenuating Nrf2/HO-1 signaling pathway

Ubiquitin-specific protease 7 (USP7), a member of the ubiquitin-specific protease (USP) family, functions as a deubiquitinating enzyme (DUB) and modulates transcriptional activity through interactions with various transcription factors. However, its role in osteoclastogenesis and the underlying molecular mechanisms remain incompletely understood. In this study, we demonstrate that USP7 is significantly upregulated during osteoclast differentiation and exhibits a negative correlation with osteoporosis. Genetic deletion of USP7 enhances osteoclast differentiation and bone resorption both in vitro and in vivo, whereas USP7 overexpression exerts inhibitory effects on these processes under similar experimental conditions. Moreover, USP7 deficiency promotes osteoclastogenesis and reduces bone mass in both normal and ovariectomized adult mice. Mechanistically, we observed hyperactivation of the nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPK)signaling pathways in USP7-deficient bone marrow-derived macrophages (BMMs). In contrast, USP7 overexpression significantly attenuates the receptor activator of NF-κB ligand (RANKL)-induced activation of these pathways. Additionally, our findings reveal that USP7 participates in the regulation of the kelch-like ECH associated protein 1 (Keap1) -nuclear factor erythroid 2-related factor 2 (Nrf2) signaling axis. USP7 knockout results in elevated intracellular reactive oxygen species (ROS) levels, while USP7 overexpression effectively reduces ROS accumulation. Collectively, these results suggest that USP7 regulates osteoclast differentiation via modulation of the NF-κB/MAPK and Nrf2 signaling pathways, thereby influencing the progression of osteoporosis.