IL-1β inhibition combined with cholesterol-lowering therapies decreases synovial lining thickness and spontaneous cartilage degeneration in a humanized dyslipidemia mouse model

• Published in: Osteoarthritis and cartilage Vol. 31; no. 3; pp. 340 - 350
• Main Authors: van Gemert, Y., Kruisbergen, N.N.L., Blom, A.B., van den Bosch, M.H.J., van der Kraan, P.M., Pieterman, E.J., Princen, H.M.G., van Lent, P.L.E.M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-03-2023
• Subjects: Animal model; Animals; Atorvastatin; Cartilage - metabolism; Cholesterol; Cholesterol - metabolism; Disease Models, Animal; Dyslipidemias; Female; IL-1β; Inflammation; Metabolic syndrome; Mice; Osteoarthritis; Osteoarthritis - metabolism; Proprotein Convertase 9; Synovitis; Systemic inflammation; Animal model; Metabolic syndrome; IL-1β; Osteoarthritis; Systemic inflammation; Cholesterol
• ISSN: 1063-4584; 1522-9653
• DOI: 10.1016/j.joca.2022.09.014

Both systemic inflammation and dyslipidemia contribute to osteoarthritis (OA) development and have been suggested as a possible link between metabolic disease and OA development. Recently, the CANTOS trial showed a reduction in knee and hip replacements after inhibition of IL-1β in patients with a history of cardiovascular disease and high inflammatory risk. In this light, we investigated whether inhibition of IL-1β combined with cholesterol-lowering therapies can reduce OA development in dyslipidemic APOE∗3Leiden mice under pro-inflammatory dietary conditions.
Female ApoE3∗Leiden mice were fed a cholesterol-supplemented Western-Type diet (WTD) for 38 weeks. After 14 weeks, cholesterol-lowering and anti-inflammatory treatments were started. Treatments included atorvastatin alone or with an anti-IL1β antibody, and atorvastatin combined with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor alirocumab without or with the anti-IL1β antibody. Knee joints were analyzed for cartilage degradation, synovial inflammation and ectopic bone formation using histology at end point.
Cholesterol-lowering treatment successfully decreased systemic inflammation in dyslipidemic mice, which was not further affected by inhibition of IL-1β. Synovial thickening and cartilage degeneration were significantly decreased in mice that received cholesterol-lowering treatment combined with inhibition of IL-1β (P < 0.01, P < 0.05, respectively) compared to mice fed a WTD alone. Ectopic bone formation was comparable between all groups.
These results indicate that inhibition of IL-1β combined with cholesterol-lowering therapy diminishes synovial thickening and cartilage degeneration in mice and may imply that this combination therapy could be beneficial in patients with metabolic inflammation.