[en] Ageing-related failure of homeostasis mechanisms, such as defects of autophagy and accumulation of senescent cells, contributes to articular cartilage degeneration and osteoarthritis (OA), for which disease-modifying treatments are not available. Our objective in this Thesis Doctoral was to identify compounds to prevent OA by regulating chondrocyte senescence and autophagy. For that, human chondrocytes were treated with IL-6, a proinflammatory cytokine present in the secretome of senescent cells, to induce senescence and inhibit autophagy flux. For high-throughtput screening with compounds from the Prestwick Chemical Library of approved drugs, the activity of senescence associated β-Galactosidase (SA-β-gal) and LC3 marker were used as marker of senescence and autophagic flux, respectively. As a result, 14 compounds were identified with senotherapeutic and pro-autophagic activity, of which Fenofibrate (FN), a fibrate and PPARα agonist used in the treatment of dyslipidemia in humans, was chosen for confirmation given the relavance of its mechanism of metabolic action. 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 for the treatment of OA. The results showed that FN selectively eliminated senescent cells via apoptosis, increased autophagic flux and protected against cartilage degradation. 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, in human patients with knee OA from the Osteoarthritis Initiative (OAI) Cohort, fibrate treatment improved OA clinical conditions. These results demonstrate that fibrates, approved drugs targeting lipid metabolism, could have immediate clinically utility for age-related cartilage degeneration and OA treatment.

[gl] Os fallos nos mecanismos de homeostase relacionados coa idade, como o defecto de autofaxia e a acumulación de células senescentes, contribúen á dexeneración da cartilaxe e á artrose (OA), para a cal no existen fármacos modificadores da enfermidade. O noso obxectivo desta Tesis Doutoral foi identificar compostos reguladores de ambos procesos para o tratamento da OA. Para iso, os condrócitos humanos foron tratados con IL-6, unha citoquina pro-inflamatoria presente no secretoma das células en estado de senescencia, para inducir senescencia e inhibir o fluxo de autofaxia. Para a realización dun cribado de alto rendemento con compostos da quimioteca de reposicionamento Prestwick de medicamentos aprobados, a actividade asociada á senescencia β-Galactosisada (SA-β-Gal) e o marcador LC3 foron empregados como marcadores de senescencia e de fluxo de autofaxia, respectivamente. Como resultado identificáronse 14 compostos con actividade senoterapéutica e pro-autofáxica, dos cales escolleuse para a súa confirmación o Fenofibrato (FN), un fibrato e agonista PPARα empleado no tratamento das dislipemias en humanos, para a súa confirmación dada a relevancia do seu mecanismo de acción metabólico. Modelos preclínicos celulares, tisulares e de sangue de pacientes artrósicos e envellecidos foron empregados para testar a eficacia e a relevancia de activar PPARα para o tratamento da OA. Os resultados mostraron que o FN eliminou selectivamente as células senescentes a través da vía de apoptose, incrementou o fluxo de autofaxia e protexeu fronte a degradación da cartilaxe. Ademais, a expresión de PPARα redúxse en ratóns envellecidos e artrósicos e en sangue e na cartilaxe procedente de pacientes con OA de rodilla. É importante destacar que nun estudio retrospectivo en pacientes con OA de rodilla procedentes da cohorte americana Osteoarthritis Initiative (OAI), o tratamento con fibratos mellorou significativamente as condicións clínicas. Estes resultados demostran que os fibratos, fármacos aprobados para o tratamento de alteracións no metabolismo lipídico, poderían ter unha inmediata utilidade clínica para o tratamento do envellecemento articular e da OA.