Duke Molecular Physiology Institute.
Department of Orthopaedic Surgery.
JCI Insight. 2019 Sep 19;4(18):129144. doi: 10.1172/jci.insight.129144.
Age is a well-established risk factor for impaired bone fracture healing. Here, we identify a role for apolipoprotein E (ApoE) in age-associated impairment of bone fracture healing and osteoblast differentiation, and we investigate the mechanism by which ApoE alters these processes. We identified that, in both humans and mice, circulating ApoE levels increase with age. We assessed bone healing in WT and ApoE-/- mice after performing tibial fracture surgery: bone deposition was higher within fracture calluses from ApoE-/- mice. In vitro recombinant ApoE (rApoE) treatment of differentiating osteoblasts decreased cellular differentiation and matrix mineralization. Moreover, this rApoE treatment decreased osteoblast glycolytic activity while increasing lipid uptake and fatty acid oxidation. Using parabiosis models, we determined that circulating ApoE plays a strong inhibitory role in bone repair. Using an adeno-associated virus-based siRNA system, we decreased circulating ApoE levels in 24-month-old mice and demonstrated that, as a result, fracture calluses from these aged mice displayed enhanced bone deposition and mechanical strength. Our results demonstrate that circulating ApoE as an aging factor inhibits bone fracture healing by altering osteoblast metabolism, thereby identifying ApoE as a new therapeutic target for improving bone repair in the elderly.
年龄是影响骨愈合的一个既定风险因素。在这里，我们发现载脂蛋白 E（ApoE）在与年龄相关的骨愈合和成骨细胞分化受损中起作用，并研究了 ApoE 改变这些过程的机制。我们发现，在人和小鼠中，循环 ApoE 水平随年龄增长而增加。我们在进行胫骨骨折手术后评估了 WT 和 ApoE-/-小鼠的骨愈合情况：ApoE-/-小鼠骨折痂中的骨沉积更高。体外重组 ApoE（rApoE）处理分化中的成骨细胞会降低细胞分化和基质矿化。此外，这种 rApoE 处理降低了成骨细胞的糖酵解活性，同时增加了脂质摄取和脂肪酸氧化。通过并体模型，我们确定循环 ApoE 在骨修复中发挥强烈的抑制作用。使用基于腺相关病毒的 siRNA 系统，我们降低了 24 月龄小鼠的循环 ApoE 水平，并证明这些老年小鼠的骨折痂显示出增强的骨沉积和机械强度。我们的结果表明，作为衰老因素的循环 ApoE 通过改变成骨细胞代谢来抑制骨骨折愈合，从而确定 ApoE 是改善老年人骨修复的新治疗靶点。
