Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
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.
Osteoarthritis Cartilage. 2021 Sep;29(9):1314-1323. doi: 10.1016/j.joca.2021.02.570. Epub 2021 Mar 12.
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.
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.
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.
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.
高系统胆固醇水平与骨关节炎（OA）的发展有关。因此，他汀类药物降低胆固醇已被认为是 OA 的潜在治疗方法。我们研究了高脂血症 APOE*3Leiden.CETP 小鼠中治疗性高强度降胆固醇是否能减轻 OA 的发展。
雌性小鼠（每组 13-16 只）喂食西方饮食（WTD）38 周。13 周后，将小鼠分为基线组和五组，分别接受 WTD 单独或联合治疗：阿托伐他汀单独、联合 PCSK9 抑制剂阿里罗库单抗和/或 ANGPTL3 抑制剂依维莫司。用组织学分析膝关节软骨降解、滑膜炎症和异位骨形成。用软骨中聚集酶活性和滑膜 S100A8 表达作为软骨降解/再生和炎症的标志物。
WTD 喂养的小鼠软骨降解和活跃修复明显增加，但降胆固醇策略并不能改善软骨破坏。这与所有治疗组的聚集酶活性和 S100A8 表达相当。异位骨形成在各组之间相当，且与胆固醇水平无关。
治疗性高强度降胆固醇本身并不能减轻高脂血症 APOE*3Leiden.CETP 小鼠的软骨降解进展，且关节炎症轻微。我们提出炎症是该疾病的一个关键特征，治疗性降胆固醇策略对于同时存在血脂异常和炎症的 OA 患者仍然有希望。
