Department of Molecular Genetics, University of Texas Southwestern, Dallas, TX, USA.
J Bone Miner Res. 2013 Feb;28(2):236-45. doi: 10.1002/jbmr.1757.
The primary role of apolipoprotein E (apoE) is to mediate the cellular uptake of lipoproteins. However, a new role for apoE as a regulator of bone metabolism in mice has recently been established. In contrast to mice, the human APOE gene is characterized by three common isoforms APOE ε2, ε3, and ε4 that result in different metabolic properties of the apoE isoforms, but it remains controversial whether the APOE polymorphism influences bone traits in humans. To clarify this, we investigated bone phenotypes of apoE knock-in (k.i.) mice, which express one human isoform each (apoE2 k.i., apoE3 k.i., apoE4 k.i.) in place of the mouse apoE. Analysis of 12-week-old female k.i. mice revealed increased levels of biochemical bone formation and resorption markers in apoE2 k.i. animals as compared to apoE3 k.i. and apoE4 k.i., with a reduced osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) ratio in apoE2 k.i., indicating increased turnover with prevailing resorption in apoE2 k.i. Accordingly, histomorphometric and micro-computed tomography (µCT) analyses demonstrated significantly lower trabecular bone mass in apoE2 than in apoE3 and apoE4 k.i. animals, which was reflected by a significant reduction of lumbar vertebrae maximum force resistance. Unlike trabecular bone, femoral cortical thickness, and stability was not differentially affected by the apoE isoforms. To extend these observations to the human situation, plasma from middle-aged healthy men homozygous for ε2/ε2, ε3/ε3, and ε4/ε4 (n = 21, n = 80, n = 55, respectively) was analyzed with regard to bone turnover markers. In analogy to apoE2 k.i. mice, a lower OPG/RANKL ratio was observed in the serum of ε2/ε2 carriers as compared to ε3/ε3 and ε4/ε4 individuals (p = 0.02 for ε2/ε2 versus ε4/ε4). In conclusion, the current data strongly underline the general importance of apoE as a regulator of bone metabolism and identifies the APOE ε2 allele as a potential genetic risk factor for low trabecular bone mass and vertebral fractures in humans.
载脂蛋白 E (apoE) 的主要作用是介导脂蛋白的细胞摄取。然而，apoE 作为调节小鼠骨代谢的新角色最近已经得到确立。与小鼠不同，人类 APOE 基因的特点是有三个常见的同工型 apoE ε2、ε3 和 ε4，这导致了 apoE 同工型的不同代谢特性，但 apoE 多态性是否影响人类的骨特征仍存在争议。为了阐明这一点，我们研究了表达一种人源同工型的 apoE 敲入 (k.i.) 小鼠的骨表型，这些同工型分别为 apoE2 k.i.、apoE3 k.i. 和 apoE4 k.i.。对 12 周龄雌性 k.i. 小鼠的分析表明，与 apoE3 k.i. 和 apoE4 k.i. 相比，apoE2 k.i. 动物的骨生化形成和吸收标志物水平升高，而 apoE2 k.i. 的骨保护素 (OPG)/核因子 κB 配体受体激活剂 (RANKL) 比值降低，表明在 apoE2 k.i. 中存在以吸收为主的高转换率。相应地，组织形态计量学和微计算机断层扫描 (µCT) 分析表明，apoE2 比 apoE3 和 apoE4 k.i. 动物的小梁骨量显著降低，这反映在腰椎最大力阻力的显著降低。与小梁骨不同，股骨皮质厚度和稳定性不受 apoE 同工型的差异影响。为了将这些观察结果扩展到人类情况，分析了中年健康男性的血浆，这些男性是 ε2/ε2、ε3/ε3 和 ε4/ε4 纯合子 (n=21、n=80、n=55)，并对骨代谢标志物进行了分析。与 apoE2 k.i. 小鼠类似，在血清中观察到 OPG/RANKL 比值在 ε2/ε2 携带者中低于 ε3/ε3 和 ε4/ε4 个体 (p=0.02 用于 ε2/ε2 与 ε4/ε4)。总之，当前的数据强烈强调了 apoE 作为骨代谢调节剂的普遍重要性，并确定了 APOE ε2 等位基因作为人类低小梁骨量和椎体骨折的潜在遗传危险因素。
