Background/Purpose: . Increasing evidence suggest that osteoarthritis (OA) is associated with hallmarks of ageing, including cellular senescence or defective autophagy, that could promote disease onset. The objective of this study was to identify small molecules with senolytic and pro-autophagy activity to prevent cartilage degeneration and OA.

Methods: Senescence and defective autophagy were induced in human chondrocytes (T/C28a2) by treatment with IL-6, a SASP factor, at 20ng/ml for 72 or 18 hours, respectively. Chondrocytes were incubated with compounds from Prestwick Chemical Library to identify potential senotherapeutics, using SA-β-gal activity imaging as fluorescence reporter. To identify molecules activating autophagy flux, LC3 reporter stably expressed in chondrocytes was imaged and analyzed. Confirmatory assays for senescence, autophagy, FoxO signaling pathway and inflammation were performed in primary human chondrocytes. The potential protection from degeneration was evaluated by Safranin O staining and Nitric Oxide (NO) production in human cartilage. Moreover Senolytic index was determined. PPARα was evaluated as a target mechanism in both spontaneous aging and surgically-induced OA in mice and in blood and cartilage from human OA Cohort. Furthermore, the consequences of PPARα silencing was investigated in human chondrocytes.

Results: The cell-based screen yielded 279 potential senotherapeutic compounds, 14 of which show pro-autophagy activity. Fenofibrate (FN), a PPARα agonist approved for dyslipidemia was selected as a candidate. FN reduced senescence and increased autophagic flux (p < 0.0001) in response to IL-6, and protects against senescence, defective autophagy and inflammation in human OA and aging primary chondrocytes. This protective effect was confirmed in human aging articular cartilage explants by a reduction of proteoglycans loss and NO production (p < 0.05) in response to IL-1b. Interestingly, FN present a senolytic activity represented by a reduction of the senescent cells and the total number of cells (p < 0.05). Moreover, this selective elimination was mediated by apoptosis. Furthermore, FN upregulates key homeostasis markers, such as LC3 and FoxO1 and CPT1A, gen involved in mitochondrial fatty acid beta-oxidation. These effects were also observed for structurally distinct PPARα agonists, suggesting that pharmacological modulation of PPARα may provide therapeutic benefits in OA. Interestingly, PPARα silencing induced senescence, altered homeostasis mechanisms or increases inflammation at both basal conditions or in response to IL-6 or IL-1b at 48 hours (p < 0.05). Moreover, PPARα expression was reduced with aging and OA in mice and in blood and cartilage from OA Cohort (p < 0.01). Remarkably, in a retrospective study, fibrate treatment improved OA clinical conditions in human patients from Osteoarthritis initiative (OAI) Cohort.

Conclusion: These results demonstrate that FDA-approved fibrate drugs targeting lipid metabolism protect against cartilage degeneration with aging and OA. Thus, these drugs could have immediate clinically utility for the treatment of OA and age-related cartilage degeneration.   

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fibrates-as-drugs-with-senolytic-and-autophagic-activity-for-osteoarthritis-treatment/