Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice.
Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice.
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脯氨酰羟化酶抑制剂可增加小鼠股骨骨折后的新血管生成和愈伤组织形成。
DOI：
10.1002/jor.20886
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发表时间：
2009-10
影响因子：
2.8
通讯作者：
Gilbert, Shawn R.
中科院分区：
文献类型：
--
作者：
Shen, Xing;Wan, Chao;Ramaswamy, Girish;Mavalli, Mahendra;Wang, Ying;Duvall, Craig L.;Deng, Lian Fu;Guldberg, Robert E.;Eberhart, Alan;Clemens, Thomas L.;Gilbert, Shawn R.
骨骼创伤和受损的骨骼愈合通常与血管减少有关。缺氧诱导因子α（HIF-1）是一种在发育和组织修复过程中负责激活血管生成因子的关键转录因子。脯氨酰羟化酶（PHD）是降解HIF-1的关键酶，其小分子抑制剂已被证明可激活HIF-1，并有效诱导血管生成。在这里，我们研究了几种市售PHD抑制剂对骨髓间充质干细胞（MSC）在体外和在体内稳定的骨折模型的影响。三种PHD抑制剂[去铁胺（DFO）、L-含羞草碱（L-mim）和二甲基草酰甘氨酸（DMOG）]有效地激活HIF-1靶向报告基因，在体外诱导血管内皮生长因子（VEGF）mRNA的表达，并在功能性血管生成测定中增加毛细血管发芽。在稳定的小鼠股骨骨折模型中，通过直接注射在骨折部位施加DFO和DMOG。PHD抑制在第14天增加了血管分布，并在第28天通过microCT评估增加了骨痂大小。这些结果表明，HIF激活是一种可行的方法，以增加血管和骨形成后骨骼创伤。
Skeletal trauma and impaired skeletal healing is commonly associated with diminished vascularity. Hypoxia inducible factor alpha (HIF-1) is a key transcription factor responsible for activating angiogenic factors during development and tissue repair. Small molecule inhibitors of the prolyl hydroxylase enzyme (PHD), the key enzyme responsible for degrading HIF-1, have been shown to activate HIF-1, and are effective in inducing angiogenesis. Here we examined the effects of several commercially available PHD inhibitors on bone marrow mesenchymal stromal cells (MSCs) in vitro and in a stabilized fracture model in vivo. Three PHD inhibitors [Desferrioxamine (DFO), L-mimosine (L-mim), and Dimethyloxalylglycine (DMOG)] effectively activated a HIF-1 target reporter, induced expression of vascular endothelial growth factor (VEGF) mRNA in vitro, and increased capillary sprouting in a functional angiogenesis assay. DFO and DMOG were applied by direct injection at the fracture site in a stabilized murine femur fracture model. PHD inhibition increased the vascularity at 14 days and increased callus size as assessed by microCT at 28 days. These results suggest that HIF activation is a viable approach to increase vascularity and bone formation following skeletal trauma.
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影响因子：
4.1
作者：
ALCANTARA, O;REDDY, SV;BOLDT, DH
通讯作者：
BOLDT, DH
影响因子：
2.8
作者：
Li, Ru;Stewart, Duncan J.;Schemitsch, Emil H.
通讯作者：
Schemitsch, Emil H.
影响因子：
5.6
作者：
Kanichai, Manoj;Ferguson, Damien;Campbell, Veronica A.
通讯作者：
Campbell, Veronica A.
影响因子：
2.6
作者：
Ferguson, C;Alpern, E;Helms, JA
通讯作者：
Helms, JA
影响因子：
82.9
作者：
Ceradini, DJ;Kulkarni, AR;Gurtner, GC
通讯作者：
Gurtner, GC