Novel high-intensive cholesterol-lowering therapies do not ameliorate knee OA development in humanized dyslipidemic mice.

Autor: van Gemert Y; Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands., Kozijn AE; Metabolic Health Research, TNO, Leiden, the Netherlands; Department of Orthopaedics, UMC Utrecht, Utrecht University, Utrecht, the Netherlands; Department of Rheumatology & Clinical Immunology, UMC Utrecht, Utrecht University, Utrecht, the Netherlands., Pouwer MG; Metabolic Health Research, TNO, Leiden, the Netherlands; Department of Cardiology, Leiden UMC, Leiden, the Netherlands., Kruisbergen NNL; Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands., van den Bosch MHJ; Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands., Blom AB; Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands., Pieterman EJ; Metabolic Health Research, TNO, Leiden, the Netherlands., Weinans H; Department of Orthopaedics, UMC Utrecht, Utrecht University, Utrecht, the Netherlands; Department of Biomechanical Engineering, Delft University of Technology, Delft, the Netherlands., Stoop R; Metabolic Health Research, TNO, Leiden, the Netherlands., Princen HMG; Metabolic Health Research, TNO, Leiden, the Netherlands., van Lent PLEM; Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address: peter.vanlent@radboudumc.nl.
Jazyk: angličtina
Zdroj: Osteoarthritis and cartilage [Osteoarthritis Cartilage] 2021 Sep; Vol. 29 (9), pp. 1314-1323. Date of Electronic Publication: 2021 Mar 12.
DOI: 10.1016/j.joca.2021.02.570
Abstrakt: Objective: High systemic cholesterol levels have been associated with osteoarthritis (OA) development. Therefore, cholesterol lowering by statins has been suggested as a potential treatment for OA. We investigated whether therapeutic high-intensive cholesterol-lowering attenuated OA development in dyslipidemic APOE∗3Leiden.CETP mice.
Methods: Female mice (n = 13-16 per group) were fed a Western-type diet (WTD) for 38 weeks. After 13 weeks, mice were divided into a baseline group and five groups receiving WTD alone or with treatment: atorvastatin alone, combined with PCSK9 inhibitor alirocumab and/or ANGPTL3 inhibitor evinacumab. Knee joints were analysed for cartilage degradation, synovial inflammation and ectopic bone formation using histology. Aggrecanase activity in articular cartilage and synovial S100A8 expression were determined as markers of cartilage degradation/regeneration and inflammation.
Results: Cartilage degradation and active repair were significantly increased in WTD-fed mice, but cholesterol-lowering strategies did not ameliorate cartilage destruction. This was supported by comparable aggrecanase activity and S100A8 expression in all treatment groups. Ectopic bone formation was comparable between groups and independent of cholesterol levels.
Conclusions: Intensive therapeutic cholesterol lowering per se did not attenuate progression of cartilage degradation in dyslipidemic APOE∗3Leiden.CETP mice, with minor joint inflammation. We propose that inflammation is a key feature in the disease and therapeutic cholesterol-lowering strategies may still be promising for OA patients presenting both dyslipidemia and inflammation.
(Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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