Jason Schutt

Background: Osteoarthritis (OA) is the most common joint pathology in the world, with increasing rates of diagnosis increasing annually. OA manifests itself as the degradation of articular cartilage, inflammation of the joint, and remodeling of the bone ^[1]. While much is known about the disease, there lacks a disease modifying therapeutic to improve outcomes of those with the disease. One potential target for potential therapeutics is Sirtuin6 (Sirt6) due to its ability to impact multiple pathways that contribute to OA.

Methods: A database search in PubMed was performed using the search terms “Sirt6 and osteoarthritis” with the exclusion criteria limiting the results to those published in the past 5 years.

Results: The studies reviewed provided a complex approach to Sirt6 and its ability to attenuate OA. One of the mechanisms for the progression of OA is the accumulation of senescent chondrocytes, leading to increased pro-inflammatory cytokines. In a trial comparing Sirt6 KO mice to control, Sirt6 KO mice showed greater loss of cartilage and chondrocyte cellularity while also showing a greater expression of pro-senescent features (p16, p21, p53), displaying how Sirt6 expression could affect the progression of OA ^[1]. Continuing, when chondrocytes were irradiated to induce DNA damage, those treated with a Sirt6 activator saw significantly less DNA damage, cellular senescence, and pro-inflammatory cytokines ^[2]. However, Sirt6 also has profound effects on macrophages, which can lead to inflammation seen in OA. Studies showed that pro-inflammatory cytokines could reduce the expression of Sirt6 ^[3].  On the other hand, cells injected with a Sirt6 inhibitor also saw increased pro-inflammatory cytokines, leading to a complex disease dynamic ^[3]. In another study, Sirt6 KO mice also were shown to have significant reductions in articular cartilage, greater osteophyte formation, and reduced expression of pro-anabolic pathways (IGF 1 / IGF-2) ^[4].  Due to its multifaceted mechanism of action, researchers explored miR-33-5p, a microRNA that was upregulated in patients with OA ^[5]. Researchers found that this microRNA targeted Sirt6 and reduced its expression. When miR-33-5p was injected into chondrocytes, they expressed greater rates of senescence, and significant decreases in articular cartilage thickness ^[5].

Conclusion: In conclusion, OA is a debilitating disease with a complicated progression. Current treatments lack the multifaceted approach to treat OA. Sirt6 has shown promise in the ability to modulate chondrocyte senescence, inflammatory cytokines, and pro-anabolic pathways. Further research exploring the exact mechanisms of Sirt6 and how to regulate its expression should be conducted.

Works Cited:

1. Ji M, Jiang H, Li Z, et al. Sirt6 attenuates chondrocyte senescence and osteoarthritis progression. Nature Communications. 2022;13(1):7658. Doi: https://doi.org/10.1038/s41467-022-35424-w
2. Copp ME, Shine J, Brown HL, et al. Sirtuin 6 activation rescues the age-related decline in DNA damage repair in primary human chondrocytes. Aging. Published online December 9, 2023. Doi: https://doi.org/10.18632/aging.205394
3. Chen J, Chen S, Cai D, Wang Q, Qin J. The role of Sirt6 in osteoarthritis and its effect on macrophage polarization. Bioengineered. 2022;13(4):9677-9689. Doi: https://doi.org/10.1080/21655979.2022.2059610
4. Collins JA, Kim CJ, Coleman A, et al. Cartilage-specific Sirt6 deficiency represses IGF-1 and enhances osteoarthritis severity in mice. Annals of the Rheumatic Diseases. 2023;82(11):1464-1473. Doi: https://doi.org/10.1136/ard-2023-224385
5. Liu Y, Zhang Z, Lu X, Liu C, Zhang H. Senescence-responsive miR-33-5p promotes chondrocyte senescence and osteoarthritis progression by targeting SIRT6. International Immunopharmacology. 2023;121:110506. Doi: https://doi.org/10.1016/j.intimp.2023.110506