Elucidation of regulatory mechanism of osteoclast differentiation and function by extracellular calcium and phosphorus.

阐明细胞外钙和磷对破骨细胞分化和功能的调节机制。

• 批准号: 12671780
• 负责人: HAKEDA Yoshiyuki
• 金额: $ 1.92万
• 依托单位: Meikai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 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/grant/KAKENHI-PROJECT-12671780/
• 关键词: osteoclasts; bone-resorbing activity; extracellular calcium; extracellular phosphorus; calcium-sensing receptor; Na; Pi cotransporter-2; 骨呼吸活性; 細胞外PO_4^<3->; Ca^<2+>感知受容体; Pi cotransporter-2

Osteoclasts are the cells primarily responsible for bone resorption, and are of hematopoietic stem cell origin. In the recent decade, regulation of osteoclastic differentiation and function by many cytokines and growth factors were extensively investigated. However, our knowledge of mechanism for regulation of osteoclasts by factors other than those cytokines and growth factors is totally poor. When osteoclasts resorb mineralized bone matrix, the cells are exposed to high concentrations of ions of calcium and phosphorus such a 40 mM from bony matrics. This evidence suggests that these ions play some roles in regulating osteoclastic differentiation and function. The aim of this project is to elucidate the physiological roles of extracellular calcium and phosghorus in osteoclastic bone resorption.Osteoclasts were isolated from unfractionated rabbit bone cells, and cultured on dentine slices. Increasing concentrations of extracellular calcium, the bone-resorbing activity of the isolated o … More steoclasts decreased dose-dependently. The value of the osteoclastic bone resorption at 20 mM of extracellular calcium was about 25% of that at normal extracellular calcium (2mM) Agonists of calcium-sensing receptor (CaSR), Gd and neomycin also decreased the osteoclastic bone resorption. In similar *anner of extracellular calcium, increase in extracellular phosphorus resulted in down-regulation of osteoclastic bone-*esorbing activity. Isolated mature osteoclasts expressed CaSR, which showed a 90% homology of nucleotide sequence of parathyroid CaSR. The osteoclasts also expressed kidney-typed Na/Pi cotransporter-2.Osteoclast progenitors differentiate into mature osteoclasts in response to M-CSF and RANKL. Increase in extracellular calcium and phosphorus dose-dependently inhibited the formation of osteoclasts from bone marrow -derived macrophages. The bone marrow-derived macrophages the same types of CaSR and Na/Pi cotransporter.In conclusions, exposure of cells of osteoclast lineage to high concentrations of extracellular calcium and phosphorus decreased formation and function of osteoclasts, implying that increase in extracellular ions following bone resorption become a terminal signal of osteoclastic bone resorption. Less

破骨细胞是主要负责骨吸收的细胞，并且是造血干细胞来源的。近十年来，许多细胞因子和生长因子对骨细胞分化和功能的调节作用得到了广泛的研究。然而，我们的知识，破骨细胞的调节机制以外的其他因素，这些细胞因子和生长因子是完全贫穷。当破骨细胞再吸收矿化的骨基质时，细胞暴露于高浓度的钙和磷离子，例如来自骨基质的40 mM。这一证据表明，这些离子在调节骨细胞分化和功能中发挥一定作用。本研究从兔未分级骨细胞中分离破骨细胞，并将其培养在牙本质切片上，以探讨细胞外钙离子和骨钙素在破骨细胞骨吸收中的生理作用。细胞外钙浓度的增加，骨吸收活性的分离， ...更多信息 破骨细胞呈剂量依赖性减少。钙敏感受体（CaSR）激动剂、Gd和新霉素也能降低骨吸收。在细胞外钙水平相似的情况下，细胞外磷水平的增加导致骨细胞骨吸收活性的下调。分离的成熟破骨细胞表达CaSR，与甲状旁腺CaSR核苷酸序列同源性为90%。破骨细胞还表达肾型Na/Pi协同转运蛋白2。破骨细胞祖细胞在M-CSF和RANKL的作用下分化为成熟的破骨细胞。细胞外钙和磷的增加剂量依赖性地抑制骨髓源性巨噬细胞破骨细胞的形成。结论：破骨细胞系细胞暴露于高浓度的细胞外钙、磷，可降低破骨细胞的形成和功能，提示骨吸收后细胞外钙、磷离子的增加是破骨细胞骨吸收的终末信号。少

项目成果

Kaneda, T.: "Endogenous pro-duction of TGF-beta is essential for osteoclastogenesis inducedby a combination of receptor activator of NF-kappa B ligand (RANKL) and macrophage-colony-stimulating factor"J.Immunol.. 165. 4254-4263 (2000)

Kaneda, T.：“TGF-β 的内源性产生对于 NF-κ B 配体受体激活剂 (RANKL) 和巨噬细胞集落刺激因子的组合诱导的破骨细胞生成至关重要”J.Immunol.. 165. 4254-

羽毛田慈之(分担執筆): "カルシウムと骨.編集:西井易穂, 森井浩世, 江澤郁子, 小島至.pp.318-321"朝倉書店. 413 (2001)

Yoshiyuki Hakeda（合著者）：“钙和骨骼。编辑：西井泰穗、森井博世、江泽郁子、小岛伊塔。第 318-321 页”朝仓书店 413 (2001)。

Nakagawa, M., Kaneda, T., Arakawa, T., Morita, S., Yamada, T., Hanada, K., Kumegawa, M., and Hakeda, Y.: "Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts"FEBS Lett.. 473. 161-164

Nakakawa, M.、Kaneda, T.、Arakawa, T.、Morita, S.、Yamada, T.、Hanada, K.、Kumekawa, M. 和 Hakeda, Y.：“血管内皮生长因子 (VEGF) 直接

Katatgiri. M., Hakeda. Y., Chikazu, D., Ogasawara, T., Takato, T.,Kumegawa, M., Nakamura, K., and Kawaguchi, H.: "Mechanism of stimulation of osteoclastic bone resorption through Gas6/Tyro 3, a receptor tyrosine kinase signaling, in mouse osteoclasts"J. B

卡塔吉里。

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