Title
Novel high-intensive cholesterol-lowering therapies do not ameliorate knee OA development in humanized dyslipidemic mice
Author
van Gemert, Y.
Kozijn, A.E.
Pouwer, M.G.
Kruisbergen, N.N.L.
van den Bosch, M.H.J.
Blom, A.B.
Pieterman, E.J.
Weinans, H.
Stoop, R.
Princen, H.M.G.
van Lent, P.L.E.M.
Publication year
2021
Abstract
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 5 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.
Subject
Western-type Diet
Cholesterol
Dyslipidemia
Mouse model
Osteoarthritis (OA)
Biomedical Innovation
Healthy Living
Life
MHR - Metabolic Health Research
ELSS - Earth, Life and Social Sciences
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http://resolver.tudelft.nl/uuid:ff6e8370-266c-4f98-b32f-5e899fa3d26b
DOI
https://doi.org/10.1016/j.joca.2021.02.570
TNO identifier
953145
Source
Osteoarthritis and Cartilage, S1063-4584
Document type
article