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

血管生成是包括骨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一致，新毛细血管的形成和矿化基质的吸收是骨形态发生和生长的重要事件。骨/软骨再吸收和血管生成之间的这种密切相互关系也发生在病理性骨疾病中，包括骨转移和类风湿性关节炎。因此，骨/软骨吸收和血管侵入的同时出现表明，可能存在调节血管生成和骨/软骨吸收的共同调节剂。本研究旨在阐明血管生成因子对破骨细胞分化和功能的调控机制：1）成熟破骨细胞表达血管内皮生长因子（VEGF）的受体（FLT 1和FLK 1）。 ...更多信息 是最有效的血管生成因子。VEGF通过上调酪氨酸磷酸化水平，增强成熟破骨细胞的存活，刺激骨吸收活性。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的骨吸收活性以及破骨细胞表型蛋白（如组织蛋白酶K和基质金属蛋白酶）的表达。9，但与VEGF的作用相反，没有提高存活率。骨吸收的刺激是通过FGF-2激活丝裂原活化蛋白激酶（MAPK）介导的。3）与FGF-2类似，血管平滑肌细胞生长因子Gas 6也依赖MAPK的激活，刺激破骨细胞的骨吸收。在破骨细胞分化过程中，Gas 6受体Tyro 3只在成熟破骨细胞中表达，而在破骨细胞祖细胞和未成熟破骨细胞中不表达，这一结果有力地表明了破骨细胞骨吸收和血管生成的共同调节。少

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