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。

• 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

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

血管生成是包括骨在内的大多数组织的发育、重建和修复所必需的。在骨骼中，破骨细胞和软骨破骨细胞等骨/软骨吸收细胞的出现与血管的侵入相一致，新的毛细血管的形成和矿化基质的吸收是骨形态发生和生长所必需的事件。这种骨/软骨吸收和血管生成之间的密切关系也存在于病理性骨疾病中，包括骨转移和类风湿性关节炎。因此，骨/软骨吸收和血管侵袭的同时出现，提示可能存在一个共同的调节因子，既调节血管生成，又调节骨/软骨吸收。1)成熟破骨细胞表达血管内皮生长因子…受体(flt1和flk1)。更重要的是，它是一种最有效的血管生成因子。2)另一种有效的血管生成因子成纤维细胞生长因子2也能促进成熟破骨细胞的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，但不能提高成骨细胞的存活率。成纤维细胞生长因子-2通过激活丝裂原活化蛋白激酶(MAPK)来刺激骨吸收。3)与成纤维细胞生长因子-2类似，血管平滑肌细胞生长因子Gas6依赖于MAPK的激活而刺激破骨细胞性骨吸收。在破骨细胞分化过程中，Gas6、Tyro 3受体仅在成熟破骨细胞中表达，而在破骨祖细胞和未成熟破骨细胞中不表达。综上所述，本项目的结果有力地表明了破骨细胞性骨吸收和血管生成的共同调节。较少

项目成果

Nakagawa,M.,Kumegawa,M.,Hakeda,Y., et al.: "Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone-resorbing activity through VEGF receptors expressed on mature osteoclasts."FEBS Lett.. 473. 161-164 (2000)

Nakakawa,M.、Kumekawa,M.、Hakeda,Y. 等人：“血管内皮生长因子 (VEGF) 通过成熟破骨细胞上表达的 VEGF 受体直接增强破骨细胞骨吸收活性。”FEBS Lett.. 473. 161

Kaneda, T., Nojima, T., Nakagawa, M., Ogasawara, A., Kaneko, H. Sato, T., Mano, H., Kumegawa, M., and Hakeda, Y.: "Endogenous production of TGF-beta is essential for osteoclastogenesis induced by a combination of receptor activator of NF-kB ligand and mac

Kaneda, T.、Nojima, T.、Nakakawa, M.、Ogasawara, A.、Kaneko, H. Sato, T.、Mano, H.、Kumekawa, M. 和 Hakeda, Y.：“TGF 的内源产生

Chikazu, D.: "Fibroblast growth factor (FGF)-2 directly stimulates mature osteoclast function through activation of FGF receptor 1 and p42/44 MAP kinase"J. Biol. Chem.. 275. 31444-31450 (2000)

Chikazu, D.：“成纤维细胞生长因子 (FGF)-2 通过激活 FGF 受体 1 和 p42/44 MAP 激酶直接刺激成熟的破骨细胞功能”J.

Chikazu, D.: "Fibroblast growth factor-2 directly stimulates mature osteoclast function through autophosphorylation of FGF receptor-1"J.Biol.Chem.. 275. 31444-31450 (2000)

Chikazu, D.：“成纤维细胞生长因子-2 通过 FGF 受体 1 的自磷酸化直接刺激成熟破骨细胞功能”J.Biol.Chem.. 275. 31444-31450 (2000)

Katagiri, M.: "Mechanism of stimulation of osteoclastic bone resorption through Gas6/Tyro 3, receptor tyrosine kinase signaling, in mouse osteoclasta"J.Biol.Chem.. 276. 7376-7382 (2001)

Katagiri, M.：“小鼠破骨细胞中通过 Gas6/Tyro 3、受体酪氨酸激酶信号传导刺激破骨细胞骨吸收的机制”J.Biol.Chem.. 276. 7376-7382 (2001)