Endothelial Notch activity promotes angiogenesis and osteogenesis in bone.
Endothelial Notch activity promotes angiogenesis and osteogenesis in bone.
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DOI：
10.1038/nature13146
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发表时间：
2014-03-20
期刊：
影响因子：
64.8
通讯作者：
Adams RH
中科院分区：
文献类型：
--
作者：
Ramasamy SK;Kusumbe AP;Wang L;Adams RH
骨骼系统中的血管生长和成骨似乎是耦合的，这表明内皮细胞和成骨细胞之间存在分子串扰。了解连接血管生成和骨形成的机制的本质对于改善骨折愈合或预防骨量丢失具有重要意义。在这里，我们表明，在骨血管生长涉及一个专门的，组织特异性形式的血管生成。Notch信号传导促进出生后长骨中的内皮细胞增殖和血管生长，这与Notch及其配体Dll4在其他器官和肿瘤的内皮中的既定功能相反。内皮细胞特异性和可诱导的Notch信号转导基因破坏不仅损害了小鼠的骨血管形态和生长，而且还导致骨生成减少、长骨缩短、软骨细胞缺陷、骨小梁丢失和骨量减少。基于一系列的遗传实验，我们得出结论，这些突变体中的骨骼缺陷涉及缺陷的血管分泌释放的Noggin从内皮细胞，这是正调控的Notch。施用重组头蛋白（一种骨形态发生蛋白的分泌型拮抗剂）可恢复骨生长和矿化、软骨细胞成熟、小梁形成以及内皮细胞特异性Notch途径突变体中的骨祖细胞数量。这些研究结果建立了一个分子框架耦合血管生成，血管分泌信号和骨生成，这可能会证明未来的治疗应用的发展具有重要意义。
Blood vessel growth in the skeletal system and osteogenesis appear coupled suggesting the existence of molecular crosstalk between endothelial and osteoblastic cells. Understanding the nature of the mechanisms linking angiogenesis and bone formation should be of great relevance for improved fracture healing or prevention of bone mass loss. Here, we show that vascular growth in bone involves a specialised, tissue-specific form of angiogenesis. Notch signalling promotes endothelial cell proliferation and vessel growth in postnatal long bone, which is the opposite of the well-established function of Notch and its ligand Dll4 in the endothelium of other organs and tumours. Endothelial cell-specific and inducible genetic disruption of Notch signalling in mice not only impaired bone vessel morphology and growth, but also led to reduced osteogenesis, shortening of long bones, chondrocyte defects, loss of trabeculae, and decreased bone mass. Based on a series of genetic experiments, we conclude that skeletal defects in these mutants involved defective angiocrine release of Noggin from endothelial cells, which is positively regulated by Notch. Administration of recombinant Noggin, a secreted antagonist of bone morphogenetic proteins, restored bone growth and mineralisation, chondrocyte maturation, the formation of trabeculae, and osteoprogenitor numbers in endothelial cell-specific Notch pathway mutants. These findings establish a molecular framework coupling angiogenesis, angiocrine signals and osteogenesis, which may prove significant for the development of future therapeutic applications.