Experimental Rheumatology, Radboud university medical center, Nijmegen, the Netherlands.
Institute of Immunology, University of Münster, Germany.
Osteoarthritis Cartilage. 2023 Jul;31(7):934-943. doi: 10.1016/j.joca.2023.01.577. Epub 2023 Mar 8.
The association between metabolic syndrome (MetS) and osteoarthritis (OA) development has become increasingly recognized. In this context, the exact role of cholesterol and cholesterol-lowering therapies in OA development has remained elusive. Recently, we did not observe beneficial effects of intensive cholesterol-lowering treatments on spontaneous OA development in E3L.CETP mice. We postulated that in the presence of local inflammation caused by a joint lesion, cholesterol-lowering therapies may ameliorate OA pathology.
Female ApoE3∗Leiden.CETP mice were fed a cholesterol-supplemented Western type diet. After 3 weeks, half of the mice received intensive cholesterol-lowering treatment consisting of atorvastatin and the anti-PCSK9 antibody alirocumab. Three weeks after the start of the treatment, OA was induced via intra-articular injections of collagenase. Serum levels of cholesterol and triglycerides were monitored throughout the study. Knee joints were analyzed for synovial inflammation, cartilage degeneration, subchondral bone sclerosis and ectopic bone formation using histology. Inflammatory cytokines were determined in serum and synovial washouts.
Cholesterol-lowering treatment strongly reduced serum cholesterol and triglyceride levels. Mice receiving cholesterol-lowering treatment showed a significant reduction in synovial inflammation (P = 0.008, WTD: 95% CI: 1.4- 2.3; WTD + AA: 95% CI: 0.8- 1.5) and synovial lining thickness (WTD: 95% CI: 3.0-4.6, WTD + AA: 95% CI: 2.1-3.2) during early-stage collagenase-induced OA. Serum levels of S100A8/A9, MCP-1 and KC were significantly reduced after cholesterol-lowering treatment (P = 0.0005, 95% CI: -46.0 to -12.0; P = 2.8 × 10, 95% CI: -398.3 to -152.1; P = 2.1 × 10, -66.8 to -30.4, respectively). However, this reduction did not reduce OA pathology, determined by ectopic bone formation, subchondral bone sclerosis and cartilage damage at end-stage disease.
This study shows that intensive cholesterol-lowering treatment reduces joint inflammation after induction of collagenase-induced OA, but this did not reduce end stage pathology in female mice.
代谢综合征（MetS）与骨关节炎（OA）发展之间的关联已逐渐得到认可。在这种情况下，胆固醇及其降脂治疗在 OA 发展中的确切作用仍不清楚。最近，我们在 E3L.CETP 小鼠中未观察到强化降脂治疗对自发性 OA 发展的有益作用。我们推测，在关节损伤引起的局部炎症的情况下，降脂治疗可能会改善 OA 病理。
雌性 ApoE3∗Leiden.CETP 小鼠喂食富含胆固醇的西式饮食。3 周后，一半的小鼠接受阿托伐他汀和抗 PCSK9 抗体阿利鲁单抗的强化降脂治疗。治疗开始 3 周后，通过关节内注射胶原酶诱导 OA。在整个研究过程中监测血清胆固醇和甘油三酯水平。使用组织学分析膝关节的滑膜炎症、软骨退化、软骨下骨硬化和异位骨形成。测定血清和滑膜冲洗液中的炎性细胞因子。
降脂治疗可显著降低血清胆固醇和甘油三酯水平。接受降脂治疗的小鼠滑膜炎症显著减少（P=0.008，WTD：95%CI：1.4-2.3；WTD+AA：95%CI：0.8-1.5），滑膜衬里厚度减少（WTD：95%CI：3.0-4.6，WTD+AA：95%CI：2.1-3.2）在早期胶原酶诱导的 OA 期间。降脂治疗后，血清 S100A8/A9、MCP-1 和 KC 水平显著降低（P=0.0005，95%CI：-46.0 至-12.0；P=2.8×10，95%CI：-398.3 至-152.1；P=2.1×10，-66.8 至-30.4）。然而，这一减少并没有减少终末期疾病时异位骨形成、软骨下骨硬化和软骨损伤所确定的 OA 病理。
本研究表明，强化降脂治疗可减轻胶原酶诱导的 OA 诱导后关节炎症，但不能减轻雌性小鼠的终末期病理。
