TY - JOUR
T1 - Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy
AU - Nogueira-Recalde, Uxía
AU - Lorenzo-Gómez, Irene
AU - Blanco, Francisco J.
AU - Loza, María I.
AU - Grassi, Diego
AU - Shirinsky, Valery
AU - Shirinsky, Ivan
AU - Lotz, Martin
AU - Robbins, Paul D.
AU - Domínguez, Eduardo
AU - Caramés, Beatriz
N1 - Publisher Copyright:
© 2019 The Authors
PY - 2019/7
Y1 - 2019/7
N2 - 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-β-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 PPARα related to cartilage degeneration. Findings: Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα 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 PPARα knockdown conferred the opposite effect. Moreover, PPARα 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, Innovación 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 the validation of targets and discovery of drugs candidates to preclinical phases, Ministerio de Economía y Competitividad, by grants of the National Instiutes of Health to PDR (P01 AG043376 and U19 AG056278). We thank FOREUM Foundation for Research in Rheumatology for their support.
AB - 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-β-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 PPARα related to cartilage degeneration. Findings: Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα 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 PPARα knockdown conferred the opposite effect. Moreover, PPARα 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, Innovación 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 the validation of targets and discovery of drugs candidates to preclinical phases, Ministerio de Economía y Competitividad, by grants of the National Instiutes of Health to PDR (P01 AG043376 and U19 AG056278). We thank FOREUM Foundation for Research in Rheumatology for their support.
KW - Ageing
KW - Autophagy
KW - Osteoarthritis
KW - Screening
KW - Senescence
KW - Therapeutics
UR - http://www.scopus.com/inward/record.url?scp=85068385233&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068385233&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2019.06.049
DO - 10.1016/j.ebiom.2019.06.049
M3 - Article
C2 - 31285188
AN - SCOPUS:85068385233
SN - 2352-3964
VL - 45
SP - 588
EP - 605
JO - EBioMedicine
JF - EBioMedicine
ER -