Pantoprazole, a Proton Pump Inhibitor, Delays Fracture Healing in Mice
Pantoprazole, a Proton Pump Inhibitor, Delays Fracture Healing in Mice
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DOI：
10.1007/s00223-012-9601-x
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发表时间：
2012-06-01
影响因子：
4.2
通讯作者：
Menger, M. D.
中科院分区：
文献类型：
--
作者：
Histing, T.;Stenger, D.;Menger, M. D.
质子泵抑制剂（PPI）广泛用于治疗消化不良问题，已被证明可降低破骨细胞活性。然而，没有关于PPI是否影响骨折愈合的信息。因此，我们研究了PPI泮托拉唑对骨折修复过程中骨痂形成和生物力学的影响。在骨折后2周和5周，采用放射学、生物力学、组织形态学和蛋白质生化分析在小鼠骨折模型中分析骨愈合。21只小鼠每天接受100 mg/kg体重泮托拉唑i.p.给药。对照组（= 21）接受等量溶剂。在泮托拉唑治疗的动物中，生物力学分析显示，与对照组相比，骨折后5周弯曲刚度显著降低。这与骨痂内骨组织的量显著减少以及软骨和纤维组织的量增加有关。蛋白质印迹分析显示骨形成标志物骨形态发生蛋白（BMP）-2，BMP-4和富含半胱氨酸的蛋白（CYR61）的表达减少。此外，增殖细胞核抗原表达显著降低表明泮托拉唑治疗后细胞增殖减少。值得注意的是，骨形成标志物的表达减少与RANKL的表达显著减少相关，表明破骨细胞抑制。泮托拉唑通过影响骨形成和骨重建延迟骨折愈合。
Proton pump inhibitors (PPIs), which are widely used in the treatment of dyspeptic problems, have been shown to reduce osteoclast activity. There is no information, however, on whether PPIs affect fracture healing. We therefore studied the effect of the PPI pantoprazole on callus formation and biomechanics during fracture repair. Bone healing was analyzed in a murine fracture model using radiological, biomechanical, histomorphometric, and protein biochemical analyses at 2 and 5 weeks after fracture. Twenty-one mice received 100 mg/kg body weight pantoprazole i.p. daily. Controls ( = 21) received equivalent amounts of vehicle. In pantoprazole-treated animals biomechanical analysis revealed a significantly reduced bending stiffness at 5 weeks after fracture compared to controls. This was associated with a significantly lower amount of bony tissue within the callus and higher amounts of cartilaginous and fibrous tissue. Western blot analysis showed reduced expression of the bone formation markers bone morphogenetic protein (BMP)-2, BMP-4, and cysteine-rich protein (CYR61). In addition, significantly lower expression of proliferating cell nuclear antigen indicated reduced cell proliferation after pantoprazole treatment. Of interest, the reduced expression of bone formation markers was associated with a significantly diminished expression of RANKL, indicating osteoclast inhibition. Pantoprazole delays fracture healing by affecting both bone formation and bone remodeling.