Laboratory Animal Facility, Medical University of Innsbruck, Innsbruck, Austria.
Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria.
PLoS One. 2019 Nov 21;14(11):e0225527. doi: 10.1371/journal.pone.0225527. eCollection 2019.
Rabbits with naturally high levels of cholesterol ester transfer protein (CETP), unlike rodents, have become an interesting animal model for the study of lipid metabolism and atherosclerosis, as they have similarities to humans in lipid metabolism, cardiovascular physiology and susceptibility to develop atherosclerosis. Rodents, such as mice, are not prone to atherosclerosis as they lack the mass and activity of CETP, as a key player in lipoprotein metabolism. Recently, APOE-knockout in rabbits has been shown to promote atherosclerosis and associated premature IVD degeneration that mimic the symptoms of atherosclerosis and structural changes of IVDs in humans. Here we examined whether APOE-knockout promoted IVD degeneration in rabbits is associated with imbalanced inflammatory catabolic activities, as the underlying problem of biological deterioration that mimic the symptoms of advanced IVD degeneration in humans. We analysed in lumbar nucleus pulposus (NP) of APOE-knockout rabbits the cell viabilities and the intracellular levels of inflammatory, catabolic, anti-catabolic and anabolic proteins derogating IVD matrix. Grades of IVD degeneration were evaluated by magnetic resonance imaging. NP cells were isolated from homozygous APOE-knockout and wild-type New Zealand White rabbits of similar age. Three-dimensional cell culture with low-glucose was completed in alginate hydrogel. Cell proliferation and intracellular levels of target proteins were examined by MTT and ELISA assays. Alike human NP cells of different disc degeneration grades, NP cells of APOE-knockout and wild-type rabbits showed significantly different in vivo cell population densities (p<0.0001) and similar in vitro proliferation rates. Furthermore, they showed differences in overexpression of selective inflammatory and catabolic proteins (p<0.0001) similar to those found in human NP cells of different disc degeneration grades, such as IL-1β, TNF-α, ADAMTS-4, ADAMTS-5 and MMP-3. This study showed that premature IVD degeneration in APOE-knockout rabbits was promoted by the accumulation of selective inflammatory catabolic factors that enhanced imbalances between catabolic and anabolic factors mimicking the symptoms of advanced IVD degeneration in humans. Thus, APOE-knockout rabbits could be used as a promising model for therapeutic approaches of degenerative disc disorders.
与啮齿动物不同，天然高胆固醇酯转移蛋白 (CETP) 水平的兔子已成为脂质代谢和动脉粥样硬化研究的有趣动物模型，因为它们在脂质代谢、心血管生理学和易患动脉粥样硬化方面与人类相似。像老鼠这样的啮齿动物不容易发生动脉粥样硬化，因为它们缺乏作为脂蛋白代谢关键因子的 CETP 的质量和活性。最近，研究表明，兔 APOE 基因敲除可促进动脉粥样硬化和相关的椎间盘中枢退化，从而模拟人类动脉粥样硬化和 IVD 结构变化的症状。在这里，我们研究了 APOE 基因敲除是否会促进兔椎间盘中枢退化与不平衡的炎症分解代谢活性有关，因为这是模仿人类晚期 IVD 退化症状的生物恶化的潜在问题。我们分析了 APOE 基因敲除兔的腰椎髓核中的细胞活力以及影响 IVD 基质的炎症、分解代谢、抗分解代谢和合成代谢蛋白的细胞内水平。通过磁共振成像评估 IVD 退变程度。NP 细胞从年龄相似的纯合 APOE 基因敲除和野生型新西兰白兔中分离出来。在藻酸盐水凝胶中进行低葡萄糖的三维细胞培养。通过 MTT 和 ELISA 检测细胞增殖和目标蛋白的细胞内水平。与不同椎间盘退变程度的人类 NP 细胞一样，APOE 基因敲除和野生型兔的 NP 细胞的体内细胞群体密度也存在显著差异(p<0.0001)，体外增殖率相似。此外，它们在选择性炎症和分解代谢蛋白的过度表达方面存在差异(p<0.0001)，与不同椎间盘退变程度的人类 NP 细胞相似，如 IL-1β、TNF-α、ADAMTS-4、ADAMTS-5 和 MMP-3。这项研究表明，APOE 基因敲除兔的椎间盘中枢过早退化是由选择性炎症分解代谢因子的积累促进的，这些因子加剧了分解代谢和合成代谢因子之间的失衡，从而模拟了人类晚期 IVD 退化的症状。因此，APOE 基因敲除兔可能成为退行性椎间盘疾病治疗方法的有前途的模型。
Oncotarget. 2017-1-17
Int J Mol Sci. 2023-1-25
J Orthop Surg Res. 2022-2-15
Atherosclerosis. 2015-12-9
Eur Cell Mater. 2015-9-21
Transgenic Res. 2015-4
Zotero 插件