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

血管生成是包括骨骼在内的大多数组织的发育、重塑和修复所必需的。在骨骼中，破骨细胞和破软骨细胞等骨/软骨吸收细胞的出现与血管侵入、新毛细血管的形成和骨吸收相一致。矿化基质是骨形态发生和生长的重要事件，骨/软骨吸收和血管生成之间的这种密切的相互关系也发生在包括骨在内的病理性骨疾病中。因此，骨/软骨吸收和血管侵袭的同时发生表明可能存在调节血管生成和骨/软骨吸收的共同调节剂。在该项目中，我们阐明了调节机制。血管生成因子对破骨细胞分化和功能的影响。1) 成熟破骨细胞表达血管内皮生长因子 (VEGF) 受体（FLT1 和 FLK1）……更多，一种最有效的血管生成因子，可增强成熟破骨细胞的存活并刺激骨吸收活性，这是由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）。还刺激成熟破骨细胞骨吸收活性和破骨细胞表型蛋白（如组织蛋白酶 K 和基质金属蛋白酶 9）的表达，但并未增强与 VEGF 的作用相反，骨吸收的刺激是由 FGF-2 激活丝裂原激活蛋白激酶 (MAPK) 介导的，骨成熟细胞在 FGF 的四种受体中特异性表达 FGFR1。与 FGF-2 类似，Gas6 是一种血管平滑肌细胞生长因子，在破骨细胞分化过程中，依赖于 Gas6 受体 MAPK 的激活，刺激破骨细胞骨吸收。 Tyro 3仅在成熟的破骨细胞中表达，而不在破骨细胞祖细胞和未成熟的破骨细胞中表达。总之，该项目中获得的结果强烈表明破骨细胞骨吸收和血管生成的共同调节。