State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Int Immunopharmacol. 2023 May;118:110075. doi: 10.1016/j.intimp.2023.110075. Epub 2023 Mar 28.
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.
骨骼结构和功能的稳定涉及多种细胞间和分子间的相互作用，其中翻译后修饰（如泛素化和去泛素化）的调节功能不容小觑。泛素特异性蛋白酶（USP）作为最大的去泛素化酶家族之一，通过多种经典成骨和溶骨信号通路（如 BMP/TGF-β 通路、NF-κB/p65 通路、EGFR-MAPK 通路和 Wnt/β-catenin 通路）参与骨稳态和骨相关疾病的发生发展。同时，USP 还可能广泛调节激素表达水平、细胞增殖和分化，并可能通过转录因子的基因融合和核转位进一步从基因水平影响骨稳态。目前，患有骨相关疾病的患者数量巨大，探索其发病机制和靶向治疗已成为热点话题。炎症介质（如 IL-1β 和 TNF-α）水平病理性升高会导致骨关节炎、类风湿关节炎和牙周炎等炎症性骨病。而机体代谢受损则会大大增加骨质疏松症的发生概率。骨相关细胞的异常生理活动会导致各种骨肿瘤。USP 在骨相关疾病中的调节作用在最近的研究中受到学术界的特别关注。在本文中，我们重点介绍了 USP 在骨稳态和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。
