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
Cellular senescence is an irreversible side effect of some pharmaceuticals which can contribute to tissue degeneration. Objective To determine whether pharmaceutical glucocorticoids induce senescence in tenocytes. Methods Features of senescence (β-galactosidase activity at pH 6 (SA-β-gal) and active...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
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BMJ Publishing Group
2014
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| _version_ | 1797074190083293184 |
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| author | Poulsen, R Watts, A Murphy, R Snelling, S Carr, A Hulley, P |
| author_facet | Poulsen, R Watts, A Murphy, R Snelling, S Carr, A Hulley, P |
| author_sort | Poulsen, R |
| collection | OXFORD |
| description | Cellular senescence is an irreversible side effect of some pharmaceuticals which can contribute to tissue degeneration. Objective To determine whether pharmaceutical glucocorticoids induce senescence in tenocytes. Methods Features of senescence (β-galactosidase activity at pH 6 (SA-β-gal) and active mammalian/ mechanistic target of rapamycin (mTOR) in cell cycle arrest) as well as the activity of the two main pathways leading to cell senescence were examined in glucocorticoid-treated primary human tenocytes. Evidence of senescence-inducing pathway induction in vivo was obtained using immunohistochemistry on tendon biopsy specimens taken before and 7 weeks after subacromial Depo-Medrone injection. Results Dexamethasone treatment of tenocytes resulted in an increased percentage of SA-βgal-positive cells. Levels of phosphorylated p70S6K did not decrease with glucocorticoid treatment indicating mTOR remained active. Increased levels of acetylated p53 as well as increased RNA levels of its pro-senescence effector p21 were evident in dexamethasone-treated tenocytes. Levels of the p53 deacetylase sirtuin 1 were lower in dexamethasone-treated cells compared with controls. Knockdown of p53 or inhibition of p53 activity prevented dexamethasone-induced senescence. Activation of sirtuin 1 either by exogenous overexpression or by treatment with resveratrol or low glucose prevented dexamethasone-induced senescence. Immunohistochemical analysis of tendon biopsies taken before and after glucocorticoid injection revealed a significant increase in the percentage of p53-positive cells (p=0.03). The percentage of p21-positive cells also tended to be higher post-injection (p=0.06) suggesting glucocorticoids activate the p53/p21 senescenceinducing pathway in vivo as well as in vitro. Conclusion As cell senescence is irreversible in vivo, glucocorticoid-induced senescence may result in longterm degenerative changes in tendon tissue. |
| first_indexed | 2024-03-06T23:32:44Z |
| format | Journal article |
| id | oxford-uuid:6c9f5aae-2348-4004-8a5b-b3174831216e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:32:44Z |
| publishDate | 2014 |
| publisher | BMJ Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:6c9f5aae-2348-4004-8a5b-b3174831216e2022-03-26T19:12:09ZGlucocorticoids induce senescence in primary human tenocytes by inhibition of sirtuin 1 and activation of the p53/p21 pathway: In vivo and in vitro evidenceJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6c9f5aae-2348-4004-8a5b-b3174831216eEnglishSymplectic Elements at OxfordBMJ Publishing Group2014Poulsen, RWatts, AMurphy, RSnelling, SCarr, AHulley, PCellular senescence is an irreversible side effect of some pharmaceuticals which can contribute to tissue degeneration. Objective To determine whether pharmaceutical glucocorticoids induce senescence in tenocytes. Methods Features of senescence (β-galactosidase activity at pH 6 (SA-β-gal) and active mammalian/ mechanistic target of rapamycin (mTOR) in cell cycle arrest) as well as the activity of the two main pathways leading to cell senescence were examined in glucocorticoid-treated primary human tenocytes. Evidence of senescence-inducing pathway induction in vivo was obtained using immunohistochemistry on tendon biopsy specimens taken before and 7 weeks after subacromial Depo-Medrone injection. Results Dexamethasone treatment of tenocytes resulted in an increased percentage of SA-βgal-positive cells. Levels of phosphorylated p70S6K did not decrease with glucocorticoid treatment indicating mTOR remained active. Increased levels of acetylated p53 as well as increased RNA levels of its pro-senescence effector p21 were evident in dexamethasone-treated tenocytes. Levels of the p53 deacetylase sirtuin 1 were lower in dexamethasone-treated cells compared with controls. Knockdown of p53 or inhibition of p53 activity prevented dexamethasone-induced senescence. Activation of sirtuin 1 either by exogenous overexpression or by treatment with resveratrol or low glucose prevented dexamethasone-induced senescence. Immunohistochemical analysis of tendon biopsies taken before and after glucocorticoid injection revealed a significant increase in the percentage of p53-positive cells (p=0.03). The percentage of p21-positive cells also tended to be higher post-injection (p=0.06) suggesting glucocorticoids activate the p53/p21 senescenceinducing pathway in vivo as well as in vitro. Conclusion As cell senescence is irreversible in vivo, glucocorticoid-induced senescence may result in longterm degenerative changes in tendon tissue. |
| spellingShingle | Poulsen, R Watts, A Murphy, R Snelling, S Carr, A Hulley, P 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 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
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