Sirt6, a member of the Sirtuin family, is a class III histone deacetylase and a key epigenetic regulator. Its biological functions, such as deacetylation, defatty-acylation, and mono-ADP-ribosylation, play a pivotal role in regulating lifespan and fundamental aging-related processes like DNA repair, gene expression, and telomeric maintenance [3].

In various disease models, Sirt6 has shown significant impacts. In chondrocyte-specific Sirt6-deficient mice, there is exaggerated chondrocyte senescence and enhanced osteoarthritis progression, indicating Sirt6's role in attenuating these processes through inhibiting the IL-15/JAK3/STAT5 signaling [1,4]. Vascular smooth muscle cell-specific Sirt6-knocked-down mice exhibit severe vascular calcification, suggesting Sirt6 protects against this via suppressing osteogenic transdifferentiation of vascular smooth muscle cells through regulating Runx2 [2]. Podocyte-specific deletion of Sirt6 exacerbates podocyte injury and proteinuria in mouse models of diabetic nephropathy and adriamycin-induced nephropathy, as Sirt6 inhibits Notch1 and Notch4 transcription by deacetylating histone H3K9 [5].

In conclusion, Sirt6 is crucial for maintaining normal physiological functions and preventing the development of multiple diseases. Gene-knockout mouse models, such as chondrocyte-specific, vascular smooth muscle cell-specific, and podocyte-specific Sirt6-deficient mice, have been instrumental in revealing Sirt6's role in osteoarthritis, vascular calcification, and proteinuric kidney disease respectively. These models provide valuable insights into the mechanisms underlying these diseases and potential therapeutic strategies targeting Sirt6.

References:

1. Ji, Ming-Liang, Jiang, Hua, Li, Zhuang, Lin, Yu Cheng, Lu, Jun. 2022. Sirt6 attenuates chondrocyte senescence and osteoarthritis progression. In Nature communications, 13, 7658. doi:10.1038/s41467-022-35424-w. https://pubmed.ncbi.nlm.nih.gov/36496445/

2. Li, Wenxin, Feng, Weijing, Su, Xiaoyan, Liu, Baohua, Huang, Hui. . SIRT6 protects vascular smooth muscle cells from osteogenic transdifferentiation via Runx2 in chronic kidney disease. In The Journal of clinical investigation, 132, . doi:10.1172/JCI150051. https://pubmed.ncbi.nlm.nih.gov/34793336/

3. Liu, Gang, Chen, Haiying, Liu, Hua, Zhang, Wenbo, Zhou, Jia. 2020. Emerging roles of SIRT6 in human diseases and its modulators. In Medicinal research reviews, 41, 1089-1137. doi:10.1002/med.21753. https://pubmed.ncbi.nlm.nih.gov/33325563/

4. Collins, John A, Kim, C James, Coleman, Ashley, Freeman, Theresa A, Loeser, Richard F. 2023. Cartilage-specific Sirt6 deficiency represses IGF-1 and enhances osteoarthritis severity in mice. In Annals of the rheumatic diseases, 82, 1464-1473. doi:10.1136/ard-2023-224385. https://pubmed.ncbi.nlm.nih.gov/37550003/

5. Liu, Min, Liang, Kaili, Zhen, Junhui, Peng, Jun, Yi, Fan. 2017. Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling. In Nature communications, 8, 413. doi:10.1038/s41467-017-00498-4. https://pubmed.ncbi.nlm.nih.gov/28871079/