Department of Trauma, Hand and Reconstructive Surgery, Saarland University, 66421 Homburg, Germany; Institute for Clinical & Experimental Surgery, Saarland University, 66421 Homburg, Germany.
Department of Trauma, Hand and Reconstructive Surgery, Saarland University, 66421 Homburg, Germany; Institute for Clinical & Experimental Surgery, Saarland University, 66421 Homburg, Germany.
Exp Gerontol. 2019 Jul 15;122:1-9. doi: 10.1016/j.exger.2019.04.005. Epub 2019 Apr 16.
Fracture healing in the elderly is associated with a declined healing potential caused by multiple factors including a delay of vascularization. Erythropoietin (EPO) has been demonstrated to improve vascularization and fracture healing in adult mice. We, therefore, hypothesized that EPO in aged mice also improves fracture healing. For this purpose, EPO was given daily in a femoral fracture model in aged mice and compared to vehicle-treated controls using radiological, biomechanical, histomorphometric and Western blot techniques. Blood analyses revealed significantly higher concentrations of hemoglobin and a higher hematocrit in EPO-treated animals at 14 and 35 days after fracture. Micro-computed tomography (μCT) indicated that the fraction of bone volume/tissue volume within the callus did not differ between the two groups. However, μCT showed a 3-fold increased tissue mineral density (TMD) in the callus of EPO-treated animals compared to controls. The callus TMD of the EPO-treated animals was also 2-fold higher when compared to the TMD of the unfractured contralateral femur. Interestingly, biomechanical analyses revealed a reduced bending stiffness in femurs of EPO-treated animals at day 35. The histomorphometrically analyzed callus size and callus composition did not show significant differences between the study groups. However, Western blot analyses exhibited an increased expression of osteoprotegerin (OPG), but in particular of receptor activator of NF-κB ligand (RANKL) in the callus of the EPO-treated animals. Further histological analyses of the callus tissue showed that this was associated with an increased number of newly formed blood vessels and a higher number of tartrate-resistant acid phosphatase (TRAP) cells. Conclusion: In fracture healing of aged mice EPO treatment increases callus TMD as well as OPG and RANKL expression, indicating an accelerated bone turnover when compared to controls. However, EPO does not improve fracture healing in aged mice. The process of fracture healing may be altered by EPO due to a deterioration of the microcirculation caused by the worsened rheological properties of the blood and due to an increased bone fragility caused by the accelerated bone turnover. Thus, EPO may not be used to improve fracture healing in the elderly.
老年人骨折愈合与多种因素有关，包括血管生成延迟，导致愈合潜力下降。促红细胞生成素（EPO）已被证明可改善成年小鼠的血管生成和骨折愈合。因此，我们假设 EPO 也可改善老年小鼠的骨折愈合。为此，在老年小鼠股骨骨折模型中每天给予 EPO，并与接受载体治疗的对照组进行比较，使用放射学、生物力学、组织形态计量学和 Western blot 技术。血液分析显示，在骨折后 14 天和 35 天，EPO 治疗组的血红蛋白和血细胞比容浓度明显升高。微计算机断层扫描（μCT）显示，两组骨痂内的骨体积/组织体积分数无差异。然而，μCT 显示 EPO 治疗组的骨痂组织矿物质密度（TMD）增加了 3 倍，而对照组则增加了 2 倍。有趣的是，生物力学分析显示，EPO 治疗组的股骨弯曲刚度在第 35 天降低。组织形态计量学分析的骨痂大小和骨痂组成在研究组之间没有显著差异。然而，Western blot 分析显示 EPO 治疗组的骨保护素（OPG），尤其是核因子-κB 受体激活剂配体（RANKL）的表达增加。对骨痂组织的进一步组织学分析表明，这与新形成的血管数量增加和抗酒石酸酸性磷酸酶（TRAP）细胞数量增加有关。结论：在老年小鼠的骨折愈合中，EPO 治疗增加了骨痂 TMD 以及 OPG 和 RANKL 的表达，与对照组相比，表明骨转换加快。然而，EPO 并不能改善老年小鼠的骨折愈合。EPO 可能会改变骨折愈合的过程，因为血液的流变学特性恶化导致微循环恶化，以及骨转换加速导致骨脆性增加。因此，EPO 可能不适用于改善老年人的骨折愈合。
