Duan Xuchen, Murata Yurie, Liu Yanqiu, Nicolae Claudia, Olsen Bjorn R, Berendsen Agnes D
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA
Development. 2015 Jun 1;142(11):1984-91. doi: 10.1242/dev.117952. Epub 2015 May 14.
Vascular endothelial growth factor A (Vegfa) has important roles in endochondral bone formation. Osteoblast precursors, endothelial cells and osteoclasts migrate from perichondrium into primary ossification centers of cartilage templates of future bones in response to Vegfa secreted by (pre)hypertrophic chondrocytes. Perichondrial osteolineage cells also produce Vegfa, but its function is not well understood. By deleting Vegfa in osteolineage cells in vivo, we demonstrate that progenitor-derived Vegfa is required for blood vessel recruitment in perichondrium and the differentiation of osteoblast precursors in mice. Conditional deletion of Vegfa receptors indicates that Vegfa-dependent effects on osteoblast differentiation are mediated by Vegf receptor 2 (Vegfr2). In addition, Vegfa/Vegfr2 signaling stimulates the expression and activity of Indian hedgehog, increases the expression of β-catenin and inhibits Notch2. Our findings identify Vegfa as a regulator of perichondrial vascularity and osteoblast differentiation at early stages of bone development.
血管内皮生长因子A（Vegfa）在软骨内骨形成中发挥着重要作用。成骨细胞前体、内皮细胞和破骨细胞会响应（前）肥大软骨细胞分泌的Vegfa，从骨膜迁移至未来骨骼软骨模板的初级骨化中心。骨膜骨系细胞也会产生Vegfa，但其功能尚未完全明确。通过在体内删除骨系细胞中的Vegfa，我们证明了祖细胞来源的Vegfa对于小鼠骨膜中血管的募集和成骨细胞前体的分化是必需的。Vegfa受体的条件性缺失表明，Vegfa对成骨细胞分化的依赖性作用是由血管内皮生长因子受体2（Vegfr2）介导的。此外，Vegfa/Vegfr2信号传导刺激了印度刺猬蛋白的表达和活性，增加了β-连环蛋白的表达并抑制了Notch2。我们的研究结果表明，Vegfa是骨发育早期骨膜血管生成和成骨细胞分化的调节因子。
