Metabolic Health Research, TNO, Leiden, The Netherlands; Department of Orthopaedics, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, The Netherlands; Department of Rheumatology & Clinical Immunology, UMC Utrecht, Utrecht University, Utrecht, The Netherlands.
Metabolic Health Research, TNO, Leiden, The Netherlands.
Osteoarthritis Cartilage. 2018 Jan;26(1):95-107. doi: 10.1016/j.joca.2017.10.010. Epub 2017 Oct 24.
Human cohort studies have demonstrated a role for systemic metabolic dysfunction in osteoarthritis (OA) pathogenesis in obese patients. To explore the mechanisms underlying this metabolic phenotype of OA, we examined cartilage degradation in the knees of mice from different genetic backgrounds in which a metabolic phenotype was established by various dietary approaches.
Wild-type C57BL/6J mice and genetically modified mice (hCRP, LDLr. Leiden and ApoE*3Leiden.CETP mice) based on C57BL/6J background were used to investigate the contribution of inflammation and altered lipoprotein handling on diet-induced cartilage degradation. High-caloric diets of different macronutrient composition (i.e., high-carbohydrate or high-fat) were given in regimens of varying duration to induce a metabolic phenotype with aggravated cartilage degradation relative to controls.
Metabolic phenotypes were confirmed in all studies as mice developed obesity, hypercholesteremia, glucose intolerance and/or insulin resistance. Aggravated cartilage degradation was only observed in two out of the twelve experimental setups, specifically in long-term studies in male hCRP and female ApoE*3Leiden.CETP mice. C57BL/6J and LDLr. Leiden mice did not develop HFD-induced OA under the conditions studied. Osteophyte formation and synovitis scores showed variable results between studies, but also between strains and gender.
Long-term feeding of high-caloric diets consistently induced a metabolic phenotype in various C57BL/6J (-based) mouse strains. In contrast, the induction of articular cartilage degradation proved variable, which suggests that an additional trigger might be necessary to accelerate diet-induced OA progression. Gender and genetic modifications that result in a humanized pro-inflammatory state (human CRP) or lipoprotein metabolism (human-E3L.CETP) were identified as important contributing factors.
人体队列研究表明，全身性代谢功能障碍在肥胖患者的骨关节炎（OA）发病机制中起作用。为了探索 OA 这种代谢表型的潜在机制，我们研究了不同遗传背景的小鼠膝关节软骨降解情况，这些小鼠通过不同的饮食方法建立了代谢表型。
我们使用野生型 C57BL/6J 小鼠和基于 C57BL/6J 背景的基因修饰小鼠（hCRP、LDLr.Leiden 和 ApoE*3Leiden.CETP 小鼠），以研究炎症和脂蛋白处理改变对饮食诱导的软骨降解的影响。给予不同宏量营养素组成的高热量饮食（即高碳水化合物或高脂肪），不同的饮食方案持续时间不同，以诱导代谢表型，相对于对照组，软骨降解加重。
所有研究均证实了代谢表型，因为小鼠出现肥胖、高胆固醇血症、葡萄糖不耐受和/或胰岛素抵抗。只有在两项实验中观察到软骨降解加重，即雄性 hCRP 和雌性 ApoE*3Leiden.CETP 小鼠的长期研究中。在研究条件下，C57BL/6J 和 LDLr.Leiden 小鼠没有发展为 HFD 诱导的 OA。骨赘形成和滑膜炎评分在不同研究之间存在差异，但在不同品系和性别之间也存在差异。
长期给予高热量饮食可使各种 C57BL/6J（基于）小鼠品系一致地出现代谢表型。相反，关节软骨降解的诱导具有可变性，这表明可能需要额外的触发因素来加速饮食诱导的 OA 进展。确定了一些重要的促成因素，包括导致人类炎症状态（人 CRP）或脂蛋白代谢（人 E3L.CETP）的基因修饰以及性别。
