Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation
Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation
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DOI：
10.1172/jci61209
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发表时间：
2012-09-01
影响因子：
15.9
通讯作者：
Olsen, Bjorn R.
中科院分区：
文献类型：
--
作者：
Liu, Yanqiu;Berendsen, Agnes D.;Olsen, Bjorn R.
骨质疏松症的骨具有减少的松质骨质量、改变的骨结构和增加的骨髓脂肪。骨质疏松症患者的骨髓干细胞比对照细胞更容易分化为脂肪细胞，这表明脂肪细胞分化可能在骨质疏松症中起作用。VEGF在成骨细胞前体细胞中高度表达，并且已知其刺激骨形成。在这里，我们测试的假设，血管内皮生长因子也是一个重要的调节细胞的命运，决定是否分化产生成骨细胞或脂肪细胞。成骨细胞前体细胞中条件性VEGF缺乏的小鼠表现出骨质疏松样表型，其特征是骨量减少和骨髓脂肪增加。此外，间充质干细胞中VEGF表达减少导致成骨细胞减少和脂肪细胞分化增加。当VEGF受体1或2被敲低时，成骨细胞分化减少，但不受重组VEGF或抗VEGF中和抗体治疗的影响。我们的研究结果表明，VEGF通过调节转录因子RUNX 2和PPAR γ 2以及通过与核膜蛋白核纤层蛋白A/C的相互作用来控制间充质干细胞的分化。重要的是，我们的数据支持一个模型，即VEGF调节分化通过一个内分泌机制，这是不同的分泌VEGF及其受体的作用。
Osteoporotic bones have reduced spongy bone mass, altered bone architecture, and increased marrow fat. Bone marrow stem cells from osteoporotic patients are more likely to differentiate into adipocytes than control cells, suggesting that adipocyte differentiation may play a role in osteoporosis. VEGF is highly expressed in osteoblastic precursor cells and is known to stimulate bone formation. Here we tested the hypothesis that VEGF is also an important regulator of cell fate, determining whether differentiation gives rise to osteoblasts or adipocytes. Mice with conditional VEGF deficiency in osteoblastic precursor cells exhibited an osteoporosis-like phenotype characterized by reduced bone mass and increased bone marrow fat. In addition, reduced VEGF expression in mesenchymal stem cells resulted in reduced osteoblast and increased adipocyte differentiation. Osteoblast differentiation was reduced when VEGF receptor 1 or 2 was knocked down but was unaffected by treatment with recombinant VEGF or neutralizing antibodies against VEGF. Our results suggested that VEGF controls differentiation in mesenchymal stem cells by regulating the transcription factors RUNX2 and PPAR gamma 2 as well as through a reciprocal interaction with nuclear envelope proteins lamin A/C. Importantly, our data support a model whereby VEGF regulates differentiation through an intracrine mechanism that is distinct from the role of secreted VEGF and its receptors.