Dong Zicai, Yang Chuan, Tan Jiulin, Dou Ce, Chen Yueqi
Department of Biomedical Materials Science, Army Medical University, Chongqing 400038, China.
Department of Orthopedics, Southwest Hospital, Army Medical University, Chongqing 400038, China.
Genes Dis. 2022 Feb 12;10(3):864-876. doi: 10.1016/j.gendis.2021.12.024. eCollection 2023 May.
The skeletal system is a dynamically balanced system, which undergoes continuous bone resorption and formation to maintain bone matrix homeostasis. As an important ADP-ribosylase and NAD-dependent deacylase, SIRT6 (SIR2-like protein 6) is widely expressed on various kinds of bone cells, such as chondrocytes, osteoblasts, osteoclasts. The aberration of SIRT6 impairs gene expression (e.g., NF-κB and Wnt target genes) and cellular functions (e.g., DNA repair, glucose and lipid metabolism, telomeric maintenance), which disturbs the dynamic balance and ultimately leads to several bone-related diseases. In this review, we summarize the critical roles of SIRT6 in the onset and progression of bone-related diseases including osteoporosis, osteoarthritis, rheumatoid arthritis, and intervertebral disc degeneration, as well as the relevant signaling pathways. In addition, we discuss the advances in the development of SIRT6 activators and elucidate their pharmacological profiles, which may provide novel treatment strategies for these skeletal diseases.
骨骼系统是一个动态平衡的系统，它不断进行骨吸收和形成以维持骨基质的稳态。作为一种重要的ADP - 核糖基化酶和NAD依赖性脱酰基酶，SIRT6（类SIR2蛋白6）在各种骨细胞如软骨细胞、成骨细胞、破骨细胞中广泛表达。SIRT6的异常会损害基因表达（如NF - κB和Wnt靶基因）和细胞功能（如DNA修复、葡萄糖和脂质代谢、端粒维持），从而扰乱动态平衡并最终导致多种骨相关疾病。在本综述中，我们总结了SIRT6在包括骨质疏松症、骨关节炎、类风湿性关节炎和椎间盘退变在内的骨相关疾病的发生和发展中的关键作用，以及相关信号通路。此外，我们讨论了SIRT6激活剂开发的进展并阐明了它们的药理学特性，这可能为这些骨骼疾病提供新的治疗策略。
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