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The role of sirtuins in tendinopathy

Tendinopathies are a group of diseases causing pain or injury to tendons. At the basis of a tendinopathy there is a trauma or a functional overload of a suffering tendon: the mechanical stress triggers micro-traumatic events, which becomes pathologies when the traumatic events causing degeneration of the tissue predominate the regeneration processes.

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. Sirtuin 1 recently attracted interest in the field of articular diseases, since it was demonstrated that malfunctions of this enzyme cause the degeneration of the connective tissue, of which the tendons are made. Figure 1 shows the degeneration of the connective tissue in transgenic mice with defective sirtuin 1: immunohistochemistry images of the connective tissue (indicated by arrows) show the erosion on the surface, meanwhile the chart represents the degree of tissue degeneration in mice with defective sirtuin 1 compared to the healthy control (Gabay et al., 2013).

F:\LINDA\Mirai bay\News e Blog\Blog\Sirt1 e tendinopatie\Figura 1.JPG

In the light of these observations, we can assume that the increasing of sirtuin 1 levels can be a strategy to treat tendinopathy.

Sirtuin 1 in this kind of disease:

  • Protection from cellular senescence

The induction of sirtuin 1 expression protects tenocytes from glucocorticoid-induced senescence; glucocorticoids are prescribed to treat inflammation generally present during a tendinopathy, but, as side effects, they induce cellular senescence, which can worsen the tissue degeneration. As shown in the figure, the level of sirtuin 1 decreases in tenocytes treated with dexamethasone, a glucocorticoid drug, but increases when tenocytes are co-treated with resveratrol (a compound known to increase the expression level of sirtuin 1).

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Moreover, the percentage of senescence cells significantly decreases significantly decreases when cells are co-treated with dexamethasone and resveratrol (Poulsen et al., 2014).

  • Suppression of apoptosis

The over-expression of sirtuin 1 in tenocytes protects them from apoptosis, which happens, similarly, if they are treated with the pro-inflammatory cytokine IL-1β or deleting sirtuin 1, as shown in the figure (Busch et al., 2012).

F:\LINDA\Mirai bay\News e Blog\Blog\Sirt1 e tendinopatie\Figura 3.JPG
  • Tenogenic differentiation of mesenchymal stem cells

As shown in the following figure, overexpression of situin 1 induces the tenogenic differentiation of mesenchymal stem cells, as demonstrated by the production of compound composing the tendons, as Collagen I and III and Scx, a specific marker for tendons and ligament (Wang et al., 2018).

F:\LINDA\Mirai bay\News e Blog\Blog\Sirt1 e tendinopatie\Figura 4.JPG

In conclusion, keeping in mind the role of sirtuin 1 in tenocytes protection, the strategies aimed to increase its expression levels are interesting to treat and prevent tendinopathy.

References

Busch, F., Mobasheri, A., Shayan, P., Stahlmann, R., & Shakibaei, M. (2012). Sirt-1 is required for the inhibition of apoptosis and inflammatory responses in human tenocytes. Journal of Biological Chemistry, 287(31), 25770-25781.

Gabay, O., Sanchez, C., Dvir‐Ginzberg, M., Gagarina, V., Zaal, K. J., Song, Y., … & McBurney, M. W. (2013). Sirtuin 1 enzymatic activity is required for cartilage homeostasis in vivo in a mouse model. Arthritis & Rheumatism, 65(1), 159-166.

Poulsen, R. C., Watts, A. C., Murphy, R. J., Snelling, S. J., Carr, A. J., & Hulley, P. A. (2014). Glucocorticoids induce senescence in primary human tenocytes by inhibition of sirtuin 1 and activation of the p53/p21 pathway: in vivo and in vitro evidence. Annals of the rheumatic diseases, 73(7), 1405-1413.

Wang, D., Jiang, X., Lu, A., Tu, M., Huang, W., & Huang, P. (2018). BMP14 induces tenogenic differentiation of bone marrow mesenchymal stem cells in vitro. Experimental and Therapeutic Medicine, 16(2), 1165-1174.

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