Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover
Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover
复制标题
血管内皮生长因子通过促进血管生成和骨转换来刺激骨修复
DOI：
10.1073/pnas.152324099
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发表时间：
2002-07-23
影响因子：
11.1
通讯作者：
Filvaroff, EH
中科院分区：
文献类型：
--
作者：
Street, J;Bao, M;Filvaroff, EH
几种生长因子在骨折修复过程中以不同的时间和空间模式表达。其中，血管内皮生长因子VEGF由于其诱导新血管形成（血管生成）的能力而受到特别关注。为了确定VEGF是否是骨修复所必需的，我们在新型小鼠模型中通过软骨中间体（软骨内骨化）和直接骨修复（膜内骨化）抑制了继发性骨愈合期间的VEGF活性。用可溶性、中和性VEGF受体治疗小鼠可减少股骨骨折中的血管生成、骨形成和骨痂矿化。抑制VEGF也显著抑制胫骨皮质骨缺损的愈合，这与我们发现VEGF在成骨细胞分化中的直接自分泌作用一致。在单独的实验中，外源性VEGF增强了小鼠股骨骨折中的血管形成、骨化和新骨（骨痂）成熟，并促进了兔桡骨节段性缺损的骨桥接。我们在愈合过程中特定时间点的结果强调了VEGF在软骨内骨化与膜内骨化以及骨骼发育与骨修复中的作用。在两种不同的模型系统和物种中观察到的对外源性VEGF的反应表明，在骨损伤部位局部应用的VEGF缓释制剂可能被证明是促进人骨修复的有效疗法。
Several growth factors are expressed in distinct temporal and spatial patterns during fracture repair. Of these, vascular endothelial growth factor, VEGF, is of particular interest because of its ability to induce neovascularization (angiogenesis). To determine whether VEGF is required for bone repair, we inhibited VEGF activity during secondary bone healing via a cartilage intermediate (endochondral ossification) and during direct bone repair (intramembranous ossification) in a novel mouse model. Treatment of mice with a soluble, neutralizing VEGF receptor decreased angiogenesis, bone formation, and callus mineralization in femoral fractures. Inhibition of VEGF also dramatically inhibited healing of a tibial cortical bone defect, consistent with our discovery of a direct autocrine role for VEGF in osteoblast differentiation. In separate experiments, exogenous VEGF enhanced blood vessel formation, ossification, and new bone (callus) maturation in mouse femur fractures, and promoted bony bridging of a rabbit radius segmental gap defect. Our results at specific time points during the course of healing underscore the role of VEGF in endochondral vs. intramembranous ossification, as well as skeletal development vs. bone repair. The responses to exogenous VEGF observed in two distinct model systems and species indicate that a slow-release formulation of VEGF, applied locally at the site of bone damage, may prove to be an effective therapy to promote human bone repair.