A SIRT1-independent mechanism mediates protection against steroid-induced senescence by resveralogues in equine tenocytes.
Abstract: Tendinopathy is a common age-related disease which causes significant morbidity for both human athletes and performance horses. In the latter, the superficial digital flexor tendon is an excellent model for human tendinopathies because it is a functional homologue of the human Achilles tendon and a primary site of injuries with strong similarities to the human disease. Corticosteroids have been previously used clinically to treat tendinopathic inflammation, but they upregulate the p53-p21 axis with concomitant reductions in cell proliferation and collagen synthesis in human tenocytes. This phenotype is consistent with the induction of cellular senescence in vitro and in vivo and probably represents an important clinical barrier to their effective use. Because of the many differences in senescence mechanisms between species, this study aimed to evaluate these mechanisms after corticosteroid treatment in equine tenocytes. Exposure to clinically reflective levels of dexamethasone for 48 hours drove equine tenocytes into steroid induced senescence (SIS). This was characterised by permanent growth arrest and upregulation of p53, the cyclin dependent kinase inhibitors p21waf and p16ink4a as well as the matrix degrading enzymes MMP1, MMP2 and MMP13. SIS also induced a distinctive equine senescence associated secretory phenotype (eSASP) characterised by enhanced secretion of IL-8 and MCP-1. Preincubation with resveratrol or the potent SIRT1 activator SRT1720 prevented SIS in equine tenocytes, while treatment with the non-SIRT1 activating resveratrol analogue V29 was equally protective against SIS, consistent with a novel, as yet uncharacterised SIRT1-indendent mechanism which has relevance for the development of future preventative and therapeutic strategies.
Copyright: © 2024 Heidari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Publication Date: 2024-08-22 PubMed ID: 39172877PubMed Central: PMC11340939DOI: 10.1371/journal.pone.0309301Google Scholar: Lookup
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Summary
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This research article explores how resveralogues can effectively protect against steroid-induced senescence in equine tenocytes, a process that is seemingly independent of SIRT1. The study provides valuable insights into potential therapeutic strategies for tendinopathy – a common age-related disease in humans and performance horses.
Background and Purpose
- Tendinopathy is a prevalent age-related disease that significantly affects the quality of life of human athletes and performance horses alike. The research focuses on understanding the mechanisms underlying this disease, with interesting similarities observed between the human Achilles tendon and the horse’s superficial digital flexor tendon, both common sites of tendinopathy.
- In an attempt to manage tendinopathic inflammation, corticosteroids have been previously employed, but they’ve been found to inadvertently halt cell proliferation and collagen synthesis, thereby inducing cellular senescence in human tenocytes. This study investigates the impact of corticosteroid treatment on equine tenocytes and explores its potential role in leading to steroid-induced senescence (SIS).
Evidence of Steroid-Induced Senescence and Its Effects
- The study reports that exposing equine tenocytes to dexamethasone, a type of corticosteroid, for 48 hours led to SIS. This senescence state was observed through permanent growth arrest of the cells, increased expressions of genes related to cell cycle suppression, such as p53, p21waf, and p16ink4a, and upregulation of matrix degrading enzymes like MMP1, MMP2, and MMP13.
- Furthermore, the development of a unique equine senescence-associated secretory phenotype (eSASP) was noted, which involved the enhanced secretion of specific inflammatory mediators such as IL-8 and MCP-1.
The Protective Role of Resveratrol and Its Analogues
- The study then examined the effects of resveratrol (a natural compound known for its health benefits) and the SIRT1 activator SRT1720, which both successfully prevented SIS in equine tenocytes.
- Interestingly, the resveratrol analogue V29, which does not activate SIRT1, was also found to shield the tenocytes from SIS.
- This finding suggests that the mechanism behind this protection is independent of SIRT1 activation, implying the existence of a yet-to-be-understood protective pathway. This discovery holds relevance for the development of potential treatment and prevention strategies for tendinopathy.
Cite This Article
APA
Heidari N, Faragher RGA, Pattison G, Dudhia J, Smith RKW.
(2024).
A SIRT1-independent mechanism mediates protection against steroid-induced senescence by resveralogues in equine tenocytes.
PLoS One, 19(8), e0309301.
https://doi.org/10.1371/journal.pone.0309301 Publication
Researcher Affiliations
- Department of Clinical Sciences and Services, The Royal Veterinary College of University of London, North Mymms, Hertfordshire, United Kingdom.
- Department of Clinical Sciences and Services, The Royal Veterinary College of University of London, North Mymms, Hertfordshire, United Kingdom.
- School of Applied Sciences, University of Brighton, Brighton, East Sussex, United Kingdom.
- School of Chemistry, College of Health and Science, University of Lincoln, Lincoln, United Kingdom.
- School of Chemistry, College of Health and Science, University of Lincoln, Lincoln, United Kingdom.
MeSH Terms
- Animals
- Horses
- Sirtuin 1 / metabolism
- Cellular Senescence / drug effects
- Tenocytes / drug effects
- Tenocytes / metabolism
- Dexamethasone / pharmacology
- Resveratrol / pharmacology
- Cell Proliferation / drug effects
- Tumor Suppressor Protein p53 / metabolism
- Tendinopathy / metabolism
- Tendinopathy / pathology
- Tendinopathy / drug therapy
- Cells, Cultured
- Tendons / drug effects
- Tendons / cytology
- Tendons / metabolism
Conflict of Interest Statement
NO authors have competing interests.
References
This article includes 17 references
- Dakin SG, Dudhia J, Smith RK. Resolving an inflammatory concept: the importance of inflammation and resolution in tendinopathy.. Vet Immunol Immunopathol 2014. 158(3–4): p. 121–7.
- Dakin SG. Proresolving Mediators LXB4 and RvE1 Regulate Inflammation in Stromal Cells from Patients with Shoulder Tendon Tears.. Am J Pathol 2019. 189(11): p. 2258–2268.
- Dakin SG. Inflammation activation and resolution in human tendon disease.. Sci Transl Med 2015. 7(311): p. 311ra173.
- Poulsen RC. 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.. 2014.
- Faragher RG. Senescence in the aging process.. F1000Res 2017. 6: p. 1219.
- Faragher RGA, Heidari N, Ostler EL. Therapeutic Opportunities Presented by Modulation of Cellular Senescence.. Subcell Biochem 2023. 102: p. 175–193.
- Dudhia J. Aging enhances a mechanically-induced reduction in tendon strength by an active process involving matrix metalloproteinase activity.. Aging Cell 2007. 6(4): p. 547–56.
- Birar VC. A facile, stereoselective, one-pot synthesis of resveratrol derivatives.. Chemistry Central journal 2015. 9(1): p. 26–26.
- Latorre E. Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence.. BMC cell biology 2017. 18(1): p. 31–15.
- Kelly E. Science-in-brief: The importance of senescence in tendinopathy: New opportunities.. Equine Vet J 2020. 52(3): p. 349–351.
- Barsby T, Guest D. Transforming growth factor beta3 promotes tendon differentiation of equine embryo-derived stem cells.. Tissue Eng Part A 2013. 19(19–20): p. 2156–65.
- Birar VC. Novel resveratrol derivatives have diverse effects on the survival, proliferation and senescence of primary human fibroblasts.. Biogerontology 2020. 21(6): p. 817–826.
- Smith RK. The influence of ageing and exercise on tendon growth and degeneration—hypotheses for the initiation and prevention of strain-induced tendinopathies.. Comp Biochem Physiol A Mol Integr Physiol 2002. 133(4): p. 1039–50.
- Kim DH. Change in plasma sirtuin 1 level by injection into uterus of resveratrol in Korean cattle.. Anim Reprod 2020. 17(1): p. e20190090.
- Milne JC. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.. Nature 2007. 450(7170): p. 712–6.
- Poulsen RC, Carr AJ, Hulley PA. Protection against glucocorticoid-induced damage in human tenocytes by modulation of ERK, Akt, and forkhead signaling.. Endocrinology 2011. 152(2): p. 503–14.
- Pavey KD. Vitamin C induced decomposition of lipid hydroperoxides: direct evidence of genotoxin-DNA binding detected by QCRS.. Chem Commun (Camb) 2001(18): p. 1886–7.
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