RT Journal Article
T1 Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy
A1 Nogueira Recalde, Uxía
A1 Loza García, María Isabel
A1 Domínguez Medina, Eduardo
A1 Caramés, Beatriz
K1 Senescence
K1 Autophagy
K1 Screening
K1 Therapeutics
K1 Ageing
K1 Osteoarthritis
AB BackgroundAgeing-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.MethodsHuman 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.FindingsSenotherapeutic 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.InterpretationThese 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.FundThis 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.
PB Elsevier
YR 2019
FD 2019-07-05
LK https://hdl.handle.net/10347/45354
UL https://hdl.handle.net/10347/45354
LA eng
NO Nogueira-Recalde, U., Lorenzo-Gómez, I., Blanco, F. J., Loza, M. I., Grassi, D., Shirinsky, V., Shirinsky, I., Lotz, M., Robbins, P. D., Domínguez, E., & Caramés, B. (2019). Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy. EBioMedicine, 45, 588–605. 10.1016/j.ebiom.2019.06.049
NO 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 Institutes of Health to PDR (P01 AG043376 and U19 AG056278). We thank the FOREUM Foundation for Research in Rheumatology for their support. UNR was supported by Programa Operativo FSE Galicia 2014–2020, Xunta de Galicia, Spain, BC was supported by Miguel Servet Type II Pro- gram-CPII16/00045-A, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades, Spain. The funders had no role in study design, data collection and analysis, decision to publish, or prepa- ration of the manuscript.
DS Minerva
RD 28 abr 2026