Identificación de moléculas reguladoras del envejecimiento articular para el tratamiento de la artrosis

Abstract

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.