骨结构和功能的稳定涉及多种细胞间和分子间的相互作用，其中后转录后修饰如泛素化和去泛素化的调节功能不容低估。作为最大的去泛素化酶家族，泛素特异性蛋白酶（USPs）参与多种经典的成骨和破骨信号通路的发育，如BMP/TGF-β信号通路、NF-κB/p65信号通路、EGFR-MAPK信号通路和Wnt/β-连环蛋白信号通路。与此同时，USPs也可以广泛调节激素表达水平、细胞增殖和分化，并通过转录因子的基因融合和核转位进一步影响骨稳态。目前，患有与骨相关的疾病的患者数量巨大，探索其发病机制和靶向治疗已成为一个热门话题。炎性介质如IL-1β和TNF-α的病理性升高导致炎性骨病，如骨关节炎、类风湿关节炎和牙周炎。而身体代谢障碍极大地增加了骨质疏松症的概率。骨相关细胞的异常生理活动导致了各种骨肿瘤的发生。USPs在骨相关疾病的调节作用近年来受到学术界特别关注。在本篇综述中，我们重点关注USPs在骨稳态和与骨相关疾病中的作用和机制，以期为临床靶向治疗提供信息。版权所有©2023 Elsevier B.V.

Stabilization of bone structure and function involves multiple cell-to-cell and molecular interactions, in which the regulatory functions of post-translational modifications such as ubiquitination and deubiquitination shouldn't be underestimated. As the largest family of deubiquitinating enzymes, the ubiquitin-specific proteases (USPs) participate in the development of bone homeostasis and bone-related diseases through multiple classical osteogenic and osteolytic signaling pathways, such as BMP/TGF-β pathway, NF-κB/p65 pathway, EGFR-MAPK pathway and Wnt/β-catenin pathway. Meanwhile, USPs may also broadly regulate regulate hormone expression level, cell proliferation and differentiation, and may further influence bone homeostasis from gene fusion and nuclear translocation of transcription factors. The number of patients with bone-related diseases is currently enormous, making exploration of their pathogenesis and targeted therapy a hot topic. Pathological increases in the levels of inflammatory mediators such as IL-1β and TNF-α lead to inflammatory bone diseases such as osteoarthritis, rheumatoid arthritis and periodontitis. While impaired body metabolism greatly increases the probability of osteoporosis. Abnormal physiological activity of bone-associated cells results in a variety of bone tumors. The regulatory role of USPs in bone-related disease has received particular attention from academics in recent studies. In this review, we focuse on the roles and mechanisms of USPs in bone homeostasis and bone-related diseases, with the expectation of informing targeted therapies in the clinic.Copyright © 2023 Elsevier B.V. All rights reserved.