Inhibition of angiotensin-converting enzyme stimulates fracture healing and periosteal callus formation - role of a local renin-angiotensin system
Inhibition of angiotensin-converting enzyme stimulates fracture healing and periosteal callus formation - role of a local renin-angiotensin system
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DOI：
10.1111/j.1476-5381.2010.00651.x
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发表时间：
2010-04-01
影响因子：
7.3
通讯作者：
Menger, M. D.
中科院分区：
文献类型：
--
作者：
Garcia, P.;Schwenzer, S.;Menger, M. D.
背景和目的：肾素-血管紧张素系统(RAS)调节血压和电解质稳态。此外，还发现了“局部”组织特异性RAS，调节再生、细胞生长、细胞凋亡、炎症和血管生成。尽管RAS的成分在成骨细胞和破骨细胞中表达，但目前还没有关于RAS在骨骼中的局部表达的描述，也没有关于RAS是否参与骨折愈合的信息。因此，我们研究了RAS的关键成分血管紧张素转换酶(ACE)在骨折愈合过程中的表达和作用。实验方法：在小鼠股骨骨折模型上，动物只接受ACE抑制剂培哚普利或赋形剂的治疗。分别于骨折愈合后2、5、10周进行X射线、显微CT、组织形态计量学、免疫组织化学、Western blotting和生物力学测试分析骨折愈合情况。培哚普利治疗可降低未骨折股骨的血压和骨密度。然而，它改善了骨膜骨痂的形成，骨折间隙的骨桥接和扭转刚度。血管紧张素转换酶抑制不影响细胞增殖，但减少细胞死亡。治疗10周后，培哚普利治疗后骨痂直径和骨体积变小，表明骨重塑进入晚期。结论：本研究为骨局部RAS影响骨折愈合过程提供了证据。我们首次证明抑制血管紧张素转换酶能够加速骨愈合和重建。
Background and purpose:The renin-angiotensin system (RAS) regulates blood pressure and electrolyte homeostasis. In addition, 'local' tissue-specific RAS have been identified, regulating regeneration, cell growth, apoptosis, inflammation and angiogenesis. Although components of the RAS are expressed in osteoblasts and osteoclasts, a local RAS in bone has not yet been described and there is no information on whether the RAS is involved in fracture healing. Therefore, we studied the expression and function of the key RAS component, angiotensin-converting enzyme (ACE), during fracture healing.Experimental approach:In a murine femur fracture model, animals were treated with the ACE inhibitor perindopril or vehicle only. Fracture healing was analysed after 2, 5 and 10 weeks using X-ray, micro-CT, histomorphometry, immunohistochemistry, Western blotting and biomechanical testing.Key results:ACE was expressed in osteoblasts and hypertrophic chondrocytes in the periosteal callus during fracture healing, accompanied by expression of the angiotensin type-1 and type-2 receptors. Perindopril treatment reduced blood pressure and bone mineral density in unfractured femora. However, it improved periosteal callus formation, bone bridging of the fracture gap and torsional stiffness. ACE inhibition did not affect cell proliferation, but reduced apoptotic cell death. After 10 week treatment, a smaller callus diameter and bone volume after perindopril treatment indicated an advanced stage of bone remodelling.Conclusions:Our study provides evidence for a local RAS in bone that influenced the process of fracture healing. We show for the first time that inhibition of ACE is capable of accelerating bone healing and remodelling.