Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy

Abstract

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.

A Geroscience Perspective on COVID-19 Mortality

“…For example, it would be of great interest to understand the role of widely-known aging-related molecular pathways-mTOR signaling, IIS signaling, cell senescence-in the response to coronavirus infection and recovery from COVID-19. Geroscience has seen major strategic advances for the discovery of treatments to increase health span in laboratory organisms (23), and there is some evidence for the efficacy of longevity-derived interventions in treating acute symptoms of age-related disease at least in the lab (24,25). There can be no doubt as to the interaction of aging biology and COVID-19 mortality, and its seems likely that a better understanding of this relationship would inform not only the biology of viral susceptibility and progression to life-threatening outcomes, but also how aging creates a pernicious environment that augments the negative consequence of viral load.…”

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

“…Piperlongumine -Radiation-induced senescent astrocytes in vivo -Radiation-induced cognitive dysfunction mouse model [205] -SMARCB1 downregulation-induced senescent A375 melanoma cells -Therapy-induced A549 or H358 lung cancer cells [145] -Radiation-induced, replication exhausted and Ras-induced senescent WI38 fibroblasts [206] Curcumin -Patient-derived senescent intervertebral disc cells [207] -Radiation-induced, oncogene-induced and replication-exhausted senescent WI38 fibroblasts [208] Fisetin -Replication-exhausted senescent Ercc1−/− MEFs -Therapy-induced senescent IMR90 senescent cells -Progeroid Ercc1 −/∆ mice and aged C57BL/6 mouse models -Murine and human-derived senescent adipose tissue [209] -Senescent human umbilical vein endothelial cells [210] Metformin -Murine olfactory ensheathing cells ex vivo [211] Panobinostat -Therapy-induced senescent A549 lung and FaDu head and neck cancer cells [212] 17-DMAG -Oxidative-stress-induce primary Ercc1 −/− -progeroid Ercc1 −/∆ mouse model [213] Torin 1 -Murine senescent hepatocytes ex vivo [214] Epigallocatechin gallate (EGCG) -Senescent 3T3-L1 preadipocytes [215] Bafilomycin A1 -Therapy-induced HCT116 colorectal cancer cells [158] Azithromycin and roxithromycin -Therapy-induced senescent MRC-5 and BJ human fibroblasts [216] Fenofibrate -Senescent T/C28a2 human chondrocytes [217] Cardiac glycosides -Therapy-induced senescent A549 lung cancer cells and SK-MEL-103 melanoma cells in vitro and in vivo [218,219] Several natural and synthetic compounds have been tested for their senescence-eliminating effects in a variety of disease models. The table summarizes the primary current preclinical evidence demonstrating the senolytic agent and the experimental model used.…”

“…Fibrates are widely used for the treatment of dyslipidemia. A recent report showed that in an IL-6-induced senescence model, fenofibrate, a PPARα agonist, exerted selective killing in T/C28a2 human chondrocytes [217]. Functionally, PPARα agonism resulted in reduced proteoglycan loss in cartilage explants and exerted a protective effect against cartilage degradation, indicating its potential utility for the treatment of aging-associated osteoarthritis [217].…”

Oleate prevents palmitate-induced mitochondrial dysfunction in chondrocytes

“…However, to carry it out, it would be necessary to perform the study including samples from subjects without OA and no associated metabolic disease, whose availability is limited. This justifies the use in our study of the human chondrocyte cell line T/C-28a2, a widely used cell line in in vitro studies of osteoarthritis (52). On the other hand, an important fact to consider is the possible toxic effect of FA concentrations on cells that could alter the results of tests such as those used in this study.…”