Osteoarthritis (OA) is degenerative bone joint disease, a tough but elastic material which coats the end of the bones, reducing friction, increasing the ability to cushion impacts and improving the joint overall functionality.

Sirtuins are histones deacetylases NAD⁺ dependent, which regulate many important metabolic pathways and are involved in many biological processes, such as cell survival, senescence, proliferation, apoptosis, DNA repair and cellular metabolism. It has been largely demonstrated that sirtuins promote longevity and health, so their pharmacological targeting with specific activators is considered an interesting way to prevent age-related diseases, such as OA.

It was observed that Sirt1 expression significantly decreases in cartilages of OA (Yang et al., 2016) and rheumatoid arthritis (Hao et al., 2017) patients, as shown in the figures, demonstrating the correlation between sirtuins and these pathologies and the role that these proteins exert in the joint wellness.

In particular:

• Sirt1 increases the chondrocytes survival, the cells composing the cartilage, (Gagarina et al., 2010) and stimulates their differentiation from staminal cells (Buhrmann et al., 2014);
• Sirt1 stimulates the expression of collagen, component of the cartilage, and aggrecan, component of the cartilage and the extracellular matrix (Dvir-Ginzberg et al., 2008);

• Sirt1 has a strong anti-inflammatory effect, since it is able to inhibit the metabolic pathways related to the synovial membrane joint inflammation (Moon et al., 2013);
• Sirt1 protects the extracellular matrix from its degradation caused by proteolytic enzymes; this occurrence is age-related, but determines the cartilages worn out.

In the light of these observation, the strategies to increase the expression levels of sirtuins are interesting therapeutic target to treat articular diseases.

References

Buhrmann, C., Busch, F., Shayan, P., & Shakibaei, M. (2014). Sirtuin-1 (SIRT1) is required for promoting chondrogenic differentiation of mesenchymal stem cells. Journal of Biological Chemistry, 289(32), 22048-22062.

Dvir-Ginzberg, M., Gagarina, V., Lee, E. J., & Hall, D. J. (2008). Regulation of cartilage-specific gene expression in human chondrocytes by SirT1 and nicotinamide phosphoribosyltransferase. Journal of Biological Chemistry, 283(52), 36300-36310.

Gagarina, V., Gabay, O., Dvir-Ginzberg, M., Lee, E. J., Brady, J. K., Quon, M. J., & Hall, D. J. (2010). SirT1 enhances survival of human osteoarthritic chondrocytes by repressing PTP1B and activating the IGF receptor pathway. Arthritis and rheumatism, 62(5), 1383.

Hao, L., Wan, Y., Xiao, J., Tang, Q., Deng, H., & Chen, L. (2017). A study of Sirt1 regulation and the effect of resveratrol on synoviocyte invasion and associated joint destruction in rheumatoid arthritis. Molecular medicine reports, 16(4), 5099-5106.

Moon, M. H., Jeong, J. K., Lee, Y. J., Seol, J. W., Jackson, C. J., & Park, S. Y. (2013). SIRT1, a class III histone deacetylase, regulates TNF-α-induced inflammation in human chondrocytes. Osteoarthritis and cartilage, 21(3), 470-480.

Yang, W., Kang, X., Liu, J., Li, H., Ma, Z., Jin, X., … & Wu, S. (2016). Clock gene Bmal1 modulates human cartilage gene expression by crosstalk with Sirt1. Endocrinology, 157(8), 3096-3107.