VEGF enhancement of osteoclast survival and bone resorption involves VEGF receptor-2 signaling and beta3-integrin.
VEGF enhancement of osteoclast survival and bone resorption involves VEGF receptor-2 signaling and beta3-integrin.
复制标题
DOI：
10.1016/j.matbio.2008.06.005
复制
发表时间：
2008-09
期刊：
影响因子：
--
通讯作者：
Quanli Yang;K. Mchugh;S. Patntirapong;Xuesong Gu;Lívius Wunderlich;P. Hauschka
中科院分区：
文献类型：
--
作者：
Quanli Yang;K. Mchugh;S. Patntirapong;Xuesong Gu;Lívius Wunderlich;P. Hauschka
血管内皮生长因子依赖的血管生成是正常骨发育所必需的，并与癌症的骨转移有关。这些过程虽然依赖于破骨细胞性骨吸收，但据报道是由内皮细胞、基质成骨细胞、软骨细胞和/或肿瘤细胞介导的。在这里，我们证明了对纯化的小鼠骨髓破骨细胞前体进行血管内皮生长因子治疗，直接提高了它们的存活率、向成熟破骨细胞的分化和吸收活性。血管内皮生长因子对成熟破骨细胞的作用主要涉及血管内皮生长因子受体2(Flk1，KdR)，受体信号转导途径包括PI3-→-Akt和→-ERK途径。破骨细胞存活和吸收活性的增加与血管内皮生长因子依赖的多个下游靶标激活的Akt[糖原合成酶β、叉头转录因子FKHR和Bcl2细胞死亡拮抗剂Bad(Ser136)]和激活的ERK1/2[核糖体S6激酶，p90RSK；和Bad(Ser112)]的磷酸化有关。在成熟破骨细胞体外分化的6天中，VEGFR2基因的表达增加了20倍，而交替的受体VEGFR1和NeuroPilin-1分别减少了30倍和3倍。此外，在β3整合素缺陷小鼠制备的细胞中，血管内皮生长因子对破骨细胞存活的促进作用减弱，从而将破骨细胞中的血管内皮生长因子信号与其与细胞外基质的附着联系起来。我们的结果表明，血管内皮生长因子直接靶向破骨细胞，从而在骨发育、血管生成和肿瘤转移中发挥新的作用。
VEGF dependent angiogenesis is required for normal bone development and has been implicated in cancer metastasis to bone. These processes, while dependent on osteoclastic bone resorption, are reportedly mediated by endothelial cells, stromal osteoblasts, chondrocytes, and/or tumor cells. We demonstrate here that VEGF treatment of purified murine bone marrow osteoclast precursors directly enhances their survival, differentiation into mature osteoclasts, and resorptive activity. The actions of VEGF on mature osteoclasts principally involve the receptor VEGFR2 (Flk1, KDR), and the receptor signaling utilizes both the PI3-kinase→Akt and MEK→ERK pathways. Increased osteoclast survival and resorptive activity is correlated with VEGF-dependent phosphorylation of multiple downstream targets of activated Akt [glycogen synthase kinase, GSK-3β; forkhead transcription factor, FKHR; and the Bcl-2 antagonist of cell death, Bad (Ser136)] and activated ERK1/2 [ribosomal S6 kinase, p90RSK; and Bad (Ser112)]. Expression of the VEGFR2 gene increases 20-fold during the 6 day in vitro differentiation of mature osteoclasts from mononuclear precursors, while alternate receptors VEGFR1 and neuropilin-1, decrease 30- and 3-fold respectively. Additionally, VEGF enhancement of osteoclast survival is diminished in cells prepared from β3 integrin-deficient mice, thus associating VEGF signaling in osteoclasts with their attachment to extracellular matrix. Our results indicate that VEGF directly targets osteoclasts, thereby playing a novel role in bone development, angiogenesis, and tumor metastasis.