The physiological role of osteoclast differentiation factor.

破骨细胞分化因子的生理作用。

• 批准号: 11470393
• 负责人: UDAGAWA Nobuyuki
• 金额: $ 3.65万
• 依托单位: Showa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470393/
• 关键词: Osteoclast; Bone resorption; Osteoblast; RANKL; OPG; TNF; 1α, 25(OH)_2D_3; PTH; 骨随間質細胞; マクロファジーコロニー刺激因子

Osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of nuclear factor-κB ligand (RANKL)/osteoclast differentiation factor (ODF), inhibits both differentiation and function of osteoclasts. We previously reported that OPG-deficient mice exhibited severe osteoporosis caused by enhanced osteoclastic bone resorption. In the present study, potential roles of OPG in osteoclast differentiation were examined using a mouse co-culture system of calvarial osteoblasts and bone marrow cells prepared from OPG-deficient mice. In the absence of bone-resorbing factors, no osteoclasts were formed in co-cultures of wild-type (+/+) or heterozygous (+/-) mouse-derived osteoblasts with bone marrow cells prepared from homozygous (-/-) mice. In contrast, homozygous (-/-) mouse-derived osteoblasts strongly supported osteoclast formation in the co-cultures with homozygous (-/-) bone marrow cells even in the absence of bone-resorbing factors. Addition of OPG to the co-cultures with osteoblasts … More and bone marrow cells derived from homozygous (-/-) mice completely inhibited spontaneously occurring osteoclast formation. Adding 1α, 25-dihydroxyvitamin D3 [1α, 25(OH)2D3] to these co-cultures significantly enhanced osteoclast differentiation. In addition, bone-resorbing activity in organ cultures of fetal long bones derived from homozygous (-/-) mice was markedly increased irrespective of the presence and absence of bone-resorbing factors in comparison with that from wild-type (+/+) mice. Osteoblasts prepared from homozygous (-/-), heterozygous (+/-) and wild-type (+/+) mice constitutively expressed similar levels of RANKL mRNA, which were equally increased by the treatment with 1α, 25(OH)2D3. When homozygous (-/-) mouse-derived osteoblasts and hemopoietic cells were co-cultured, but direct contact between them was prevented, no osteoclasts were formed even in the presence of 1α, 25(OH)2D3 and M-CSF.These findings suggest that OPG produced by osteoblasts/stromal cells is a physiologically important regulator in osteoclast differentiation and function, and that RANKL expressed by osteoblasts functions as a membrane-associated form. Less

骨保护素（Osteoprotegerin， OPG）是核因子-κB配体受体激活因子(RANKL)/破骨细胞分化因子（ODF）的可溶性诱饵受体，可抑制破骨细胞的分化和功能。我们之前报道过opg缺陷小鼠表现出由破骨细胞骨吸收增强引起的严重骨质疏松症。在本研究中，我们使用从OPG缺陷小鼠制备的颅骨成骨细胞和骨髓细胞共培养系统来检测OPG在破骨细胞分化中的潜在作用。在缺乏骨吸收因子的情况下，野生型（+/+）或杂合子（+/-）小鼠来源的成骨细胞与纯合子（-/-）小鼠制备的骨髓细胞共培养均未形成破骨细胞。相比之下，纯合子（-/-）小鼠来源的成骨细胞在与纯合子（-/-）骨髓细胞共培养时，即使在没有骨吸收因子的情况下，也强烈支持破骨细胞的形成。在纯合子（-/-）小鼠骨髓细胞中加入OPG可完全抑制自发发生的破骨细胞形成。在这些共培养物中添加1α， 25-二羟基维生素D3 [1α， 25(OH)2D3]可显著增强破骨细胞的分化。此外，与野生型（+/+）小鼠相比，纯合子（-/-）小鼠的胎儿长骨器官培养物的骨吸收活性明显增加，而不考虑骨吸收因子的存在。纯合子（-/-）、杂合子（+/-）和野生型（+/+）小鼠制备的成骨细胞组成性地表达相似水平的RANKL mRNA，并在1α， 25(OH)2D3处理下均增加。当纯合子（-/-）小鼠来源的成骨细胞与造血细胞共培养，但阻止它们之间的直接接触时，即使在1α， 25(OH)2D3和M-CSF存在下，也没有形成破骨细胞。这些发现表明，成骨细胞/基质细胞产生的OPG是破骨细胞分化和功能的重要生理调节剂，成骨细胞表达的RANKL是一种膜相关形式。少

项目成果

Kobayashi, K., Takahashi, N., Jimi, E., Udagawa, N., Takami, M., Kotake, S., Nakagawa, N., Kinosaki, M., Yamaguchi, K., Shima, N., Yasuda, H., Morinaga, T., Higashio, Martin, T.J., Suda, T.: "Tumor necrosis factor α stimulates osteoclast differentiation b

小林，K.，高桥，N.，吉米，E.，宇田川，N.，高见，M.，小竹，S.，中川，N.，城崎，M.，山口，K.，志马，N.， Yasuda, H.、Morinaga, T.、Higashio, Martin, T.J.、Suda, T.：“肿瘤坏死因子 α 刺激破骨细胞分化 b

Udagawa, N., Takahashi, N., Yasuda, H., Mizuno, A., Itoh, K., Ueno, Y., Shinki, T., Gillespie, M.T., Martin, T.J., Higashio, K., Suda, T.: "Osteoprotegerin produced by osteoblasts is an important regulator in osteoclast development and function."Endocrino

宇田川，N.，高桥，N.，安田，H.，水野，A.，伊藤，K.，上野，Y.，新基，T.，吉莱斯皮，M.T.，马丁，T.J.，东尾，K.，须田，

Itoh, K., Udagawa, N., Matsuzaki, K., Takami, M., Amano, H., Shinki, T., Ueno, Y., Takahashi, N., Suda, T.: "Importance of membrane-or matrix-associated forms of M-CSF and RANKL/ODF in osteoclastogenesis supported by SaOS-4/3 cells expressing recombinant

Itoh, K.、Udakawa, N.、Matsuzaki, K.、Takami, M.、Amano, H.、Shinki, T.、Ueno, Y.、Takahashi, N.、Suda, T.：“膜的重要性-

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