دورية أكاديمية
Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy
| العنوان: | Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy |
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| المؤلفون: | Nogueira Recalde, Uxía, Lorenzo Gómez, Irene, BLANCO GARCIA, FRANCISCO JAVIER, Loza, Maria I, Grassi, Diego, Shirinsky, Valery, Shirinsky, Ivan, Lotz, Martin, Robbins, Paul D, Dominguez, Eduardo, Cerdeira Caramés, Sara |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Apoptosis, Fenofibrate, Lipid Metabolism, Mice, Chondrocytes, Animals, Osteoarthritis, Interleukin-6, Therapeutics, PPAR alpha, Autophagy, Aging, Humans, Cells, Cartilage Diseases, Cartilage, autofagia, interleucina-6, animales, PPAR alfa, condrocitos, terapéutica, enfermedades del cartílago, fenofibrato, metabolismo lipídico, cartílago, humanos, envejecimiento, células, osteoartritis |
| الوصف: | BACKGROUND: Ageing-related failure of homeostasis mechanisms contributes to articular cartilage degeneration and osteoarthritis (OA), for which disease-modifying treatments are not available. Our objective was to identify molecules to prevent OA by regulating chondrocyte senescence and autophagy. METHODS: Human chondrocytes with IL-6 induced senescence and autophagy suppression and SA-beta-gal as a reporter of senescence and LC3 as reporter of autophagic flux were used to screen the Prestwick Chemical Library of approved drugs. Preclinical cellular, tissue and blood from OA and blood from OA and ageing models were used to test the efficacy and relevance of activating PPARalpha related to cartilage degeneration. FINDINGS: Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARalpha agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and OA chondrocytes whereas PPARalpha knockdown conferred the opposite effect. Moreover, PPARalpha expression was reduced through both ageing and OA in mice and also in blood and cartilage from knees of OA patients. Remarkably, in a retrospective study, fibrate treatment improved OA clinical conditions in human patients from the Osteoarthritis Initiative (OAI) Cohort. INTERPRETATION: These results demonstrate that FDA-approved fibrate drugs targeting lipid metabolism protect against cartilage degeneration seen with ageing and OA. Thus, these drugs could have immediate clinically utility for age-related cartilage degeneration and OA treatment. FUND: This study was supported by Instituto de Salud Carlos III- Ministerio de Ciencia, Innovacion y Universidades, Spain, Plan Estatal 2013-2016 and Fondo Europeo de Desarrollo Regional (FEDER), "Una manera de hacer Europa", PI14/01324 and PI17/02059, by Innopharma Pharmacogenomics platform applied to ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2352-3964 |
| العلاقة: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642320/pdf/main.pdfTest; https://www.ncbi.nlm.nih.gov/pubmed/31285188Test; http://hdl.handle.net/20.500.11940/15929Test; 32401 |
| DOI: | 10.1016/j.ebiom.2019.06.049 |
| الإتاحة: | https://doi.org/20.500.11940/15929Test https://doi.org/10.1016/j.ebiom.2019.06.049Test https://hdl.handle.net/20.500.11940/15929Test https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642320/pdf/main.pdfTest https://www.ncbi.nlm.nih.gov/pubmed/31285188Test |
| حقوق: | Attribution-NonCommercial-NoDerivatives 4.0 International ; https://creativecommons.org/licenses/by-nc-nd/4.0Test/ ; openAccess |
| رقم الانضمام: | edsbas.E5EE18E8 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 23523964 |
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| DOI: | 10.1016/j.ebiom.2019.06.049 |