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.

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Simvastatin treatment is associated with moderate clinical improvement in patients with active RA. Immunological changes produced by simvastatin in peripheral blood are complex and may reflect both its anti- and pro-inflammatory properties.

BackgroundThere is growing evidence that mast cells (MCs) play a role in knee osteoarthritis (OA). H1-antihistamines block H1-receptors of histamine, which is an important mediator of MCs. There is a lack of data on whether H1-antihistamines can influence OA. We hypothesized that the use of H1-antihistamines may be linked to the reduced prevalence of knee OA.MethodsBaseline data from the Osteoarthritis Initiative cohort were analysed cross-sectionally. Unadjusted and adjusted logistic regression models were performed to compare the prevalence of knee OA in H1-antihistamine users and non-users. Generalized estimating equations were used to adjust for the correlation between knees. Knee OA was defined as (1) Kellgren-Lawrence (KL) grade ≥ 2 or total joint replacement or (2) KL grade ≥ 2 and joint space narrowing or total joint replacement.ResultsThe analysed sample consisted of 8545 knees (664 knees of H1-antihistamine users and 7881 knees of H1-antihistamine non-users). The use of H1-antihistamines was associated with reduced prevalence of knee OA in unadjusted and adjusted models using both the first (adjusted OR, 0.77; 95% CI, 0.62, 0.96; P < 0.02) and second (adjusted OR, 0.75; 95% CI, 0.62, 0.93; P < 0.008) definitions of knee OA.ConclusionsH1-antihistamines are associated with a reduced prevalence of knee OA. The findings indicate that this class of drugs should be further evaluated for possible structure-modifying properties in knee OA.

In recent years, peroxisome proliferator-activated receptors (PPARs) have received growing interest due to the broad spectrum of their biological activities. PPARα, an isoform of PPAR, plays an important role in lipid homeostasis and inflammation, which makes it a potential target for the treatment of chronic inflammatory disorders, including RA. This paper reviews studies on the properties of PPARα agonists which may be pertinent to the treatment of RA. These properties include effects on lipid metabolism, inflammation, and angiogenesis, as well as interference with glucocorticoid effects, and a potential role in gender dimorphism of autoimmune disorders. However, current clinical experience with this class of drugs in RA is limited. New studies are needed to elucidate whether PPARα agonism may be an effective treatment strategy for RA patients.