Department of Surgical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden.
Bone. 2013 May;54(1):126-32. doi: 10.1016/j.bone.2013.01.019. Epub 2013 Jan 19.
Fracture healing is a complex interplay between endochondral and intramembranous bone formation processes. The canonical Wnt/β-catenin pathway enhances new bone formation and may play a role in fracture healing. Glycogen synthase kinase 3β (GSK3β) is a key regulator of β-catenin degradation. In this study, we investigate the effects of AZD2858, an orally bioactive GSK3 inhibitor, on fracture healing. Femoral fractures were produced in rats after the insertion of a femoral nail. The rats were treated with oral administration of AZD2858 at a dose of 30 μmol/kg (20mg/kg) daily for up to 3 weeks, while control animals were administered vehicle. At 4days, and at 1, 2 and 3 weeks, histological analysis was performed, and at the 2 and 3 week time points, we performed peripheral quantitative computed tomography (pQCT), X-rays, and four-point bending tests. Peripheral QCT showed an increase in both mineral density (of 28% at 2 weeks and 38% at 3weeks) and mineral content (of 81% at 2 weeks and 93% at 3 weeks) in the calluses from AZD2858 treated animals as compared to vehicle treated animals. Histological analysis demonstrated that rats treated with GSK3 inhibitor healed their fractures rapidly, but without the pre-formation of cartilage tissue. Furthermore, four-point bending tests of fractured femora from animals treated for 2 and 3 weeks showed an increase in strength in treated animals compared to their vehicle-treated controls. In conclusion, AZD2858, a potent GSK3 inhibitor, has a substantial impact on fracture healing. The fractures healed with a bony callus without an obvious endochondral component, suggesting that AZD2858 drives mesenchymal cells into the osteoblastic pathway. This leads to direct bone repair in an unstable fracture milieu.
骨折愈合是一个复杂的过程，涉及软骨内和膜内骨形成过程。经典的 Wnt/β-catenin 通路增强了新骨形成，可能在骨折愈合中发挥作用。糖原合成酶激酶 3β（GSK3β）是β-catenin 降解的关键调节剂。在这项研究中，我们研究了口服生物活性 GSK3 抑制剂 AZD2858 对骨折愈合的影响。在插入股骨钉后，在大鼠的股骨中产生骨折。大鼠每天口服 AZD2858 治疗，剂量为 30μmol/kg（20mg/kg），持续 3 周，而对照组给予载体。在第 4 天，以及第 1、2 和 3 周时，进行组织学分析，在第 2 和 3 周时，进行外周定量计算机断层扫描（pQCT）、X 射线和四点弯曲测试。外周 QCT 显示，与载体处理的动物相比，AZD2858 处理的动物的骨痂中的矿物质密度（2 周时增加 28%，3 周时增加 38%）和矿物质含量（2 周时增加 81%，3 周时增加 93%）均增加。组织学分析表明，用 GSK3 抑制剂治疗的大鼠迅速愈合了骨折，但没有预先形成软骨组织。此外，用 GSK3 抑制剂治疗 2 周和 3 周的骨折股骨的四点弯曲测试显示，与载体处理的对照组相比，治疗组的强度增加。总之，强效 GSK3 抑制剂 AZD2858 对骨折愈合有显著影响。骨折通过骨痂愈合，没有明显的软骨内成分，这表明 AZD2858 促使间充质细胞进入成骨细胞途径。这导致在不稳定的骨折环境中直接进行骨修复。
