Elucidation of mechanism for regulation of osteoclastic differentiation and function by angiogenic factors.

阐明血管生成因子调节破骨细胞分化和功能的机制。

基本信息

批准号：
12470388
负责人：
KUMEGAWA Masayoshi
金额：
$ 7.1万
依托单位：
Meikai University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470388/
关键词：
osteoclast bone resolution osteoclastogenesis angiogenic factors VEGF FGF-2 FLT1 FLK1 FGFR1 骨呼吸血管新生 bFGF 骨吸収活性チロシンリン酸化 MAPK

项目摘要

Angiogenesis is required for the development, remodeling, and repairing of most tissue including bone. In skeleton, the appearance of bone/cartilage-resorbing cells such as osteoclasts and chondroclasts coincides with blood vessel invasion, and the formation of new capillaries and the resorption of mineralized matrices are essential events for bone morphogenesis and growth. This intimate interrelationship between the bone/cartilage resorption and the angiogenesis also occurs in pathological bone disorders including bone metastasis and rheumatoid arthritis. Thus, the simultaneous appearance of the bone/cartilage-resorbing and the invasion by blood vessels suggests that there may be a common modulator that regulates both angiogenesis and bone/cartilage resorption. In this project, we elucidated a mechanism for regulation of osteoclastic differentiation and function by angiogenic factors.1) Mature osteoclasts expressed receptors (FLT1 and FLK1) of vascular endothelial growth factor (VEGF) … More , a most potent angiogenic factor. VEGF enhanced the survival of mature osteoclasts and stimulated the bone-resorbing activity, which were mediated by up-regulation of tyrosine phosphorylation.2) Another potent angiogenic factor, fibroblast growth factor-2 (FGF-2) also stimulated mature osteoclastic bone-resorbmg activity and expressions of osteoclast phenotypic proteins such as cathepsin K and matrix metalloproteinase-9 but did not enhance the survival in contrast to the effect of VEGF. The stimulation of the bone resorption was mediated by the activation of mitogen-activated protein kinase (MAPK) by FGF-2. The mature osteoclasts specifically expressed FGFR1 among four receptors of FGF.3) In similar to FGF-2, Gas6, a growth factor of vascular smooth muscle cells, stimulated the osteoclastic bone resorption dependent on the activation of MAPK. In process of osteoclast differentiation, a receptor of Gas6, Tyro 3 was expressed only in mature osteoclasts but not in osteoclast progenitors and immature osteoclast.Taken together, results obtained in this project strongly indicated the common regulation of osteoclastic bone resorption and angiogenesis. Less

血管生成需要大多数组织的发育，重塑和修复包括骨骼。在骨骼中，骨/软骨敏化细胞的出现，例如破骨细胞和软骨塑料与血管侵袭相吻合，新毛细血管的形成以及矿化物质的分辨率是骨形态发生和生长的重要事件。骨/软骨分辨率与血管生成之间的这种紧密相互关系也发生在病理骨骼疾病中，包括骨转移和类风湿关节炎。这就是骨/软骨的同时出现以及血管的侵袭表明，可能有一个共同的调节剂可以调节血管生成和骨/软骨分辨率。在该项目中，我们阐明了一种通过血管生成因子调节破骨碎屑分化和功能的机制。1）成熟的骨细胞表达血管内皮生长因子（VEGF）的受体（FLT1和FLK1）……更多，更多，最有效的血管生成因子。 VEGF增强了成熟破骨细胞的存活并刺激了骨质感活性，这是通过酪氨酸磷酸化的上调介导的。2）另一种有效的血管生成因子成纤维细胞生长因子-2（FGF-2）也刺激成熟的骨质骨骼活性和蛋白酶的蛋白酶的成纤维细胞生长因子-2（FGF-2），也是如此。基质金属蛋白酶-9，但与VEGF的作用相反，但没有提高生存率。通过FGF-2激活有丝分裂原激活蛋白激酶（MAPK）的刺激是通过FGF-2的激活介导的。成熟的破骨细胞在FGF.3的四个受体中特别表达FGFR1），类似于FGF-2，GAS6，GAS6是血管平滑肌细胞的生长因子，刺激了取决于MAPK激活的破骨骨骨分辨率。在破骨细胞分化的过程中，gas6的受体3仅在成熟的破骨细胞中表达，但在破骨细胞祖细胞和未成熟的破骨细胞中不表示，在该项目中获得的结果强烈表明，在该项目中获得的结果表明，对骨质碎石的骨分辨率和天形生成的共同调节。较少的