Role of Cytokines Signaling in Osteoblastic Differentiation

细胞因子信号传导在成骨细胞分化中的作用

• 批准号: 10671739
• 负责人: NISHIMURA Riko
• 金额: $ 2.11万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671739/
• 关键词: Osteoblast; IL-6 signaling; JAK kinases; STAT; MAP kinase; BMP; Smad; Cbfa1

1) Role of IL-6 in osteoblastic differentiationWe determined whether IL-6 plays a role in osteoblastogenesis using pluripotent mesenchymal cell line C3H10T1/2. IL-6 induced osteoblastic differentiation of C3H10T1/2 in the presence of sIL-6R, but not in the absence of it. One of IL-6 family cytokine, Oncostatin M also showed quite similar effects on C3H10T1/2. The data suggest that IL-6/sIL-6R is involved in osteoblastic differentiation of pluripotent mesenchymal cells.2) Activation of IL-6 signaling during osteoblactic differentiationTo understand the molecular mechanisms by which IL-6 differentiates C3H10T1/2 into osteoblastic cells, we first determined the intracellular signaling cascade of IL-6 in C3H10T1/2. IL-6/sIL-6R induced tyrosine phosphorylation of gp130, JAK1, and JAK2. STAT1 and STAT3 were tyrosine-phosphorylated by IL-6/sIL-6R treatment, and translocated from cytoplasm into nucleus. IL-6/sIL-6R also activated MAP kinase. These results indicate that IL-6/sIL-6R concomitantl … More y activate JAK/STAT and MAP kinase pathway in C3H10T1/2.3) Role of JAK/STAT and MAP kinase signaling in osteoblastic differentiationIn order to investigate the functional role of JAK/STAT signaling in osteoblastic differentiation, we examined the effects of dominant negative JAK1 (DN-JAK1) or JAK2 (DN-JAK2) on IL-6 induced osteoblastic differentiation. DN-JAK1 as well as DN-JAK2 blocked activation of JAK/STAT signaling. DN-JAK1 and DN-JAK2 also blocked IL-6 induced osteoblastic differentiation of C3H10T1/2. We, next, studied the role of MAP kinases in osteoblastic differentiation using dominant negative ras (DN-ras). DN-ras inhibited activation of MAP kinases. DN-ras partially inhibited activation of STAT and osteoblastic differentiation of C3H10T1/2. The data indicated that essential role of JAK/STAT signaling and the involvement of cross talk between JAK/STAT and MAP kinase signaling in osteoblastic differentiation induced by IL-6.4) BMP2 signaling that regulates osteoblastic differentiationWe found BMP2 induced osteoblastic differentiation by inducing expression of Cbfa1 via activation of Smad signaling. Less

1)IL-6在成骨细胞分化中的作用我们用多能间充质细胞系C3H10T1/2研究了IL-6在成骨细胞分化中的作用。作为IL-6家族细胞因子之一的抑瘤素M对C3H10T1/2的作用也非常相似。提示IL-6/sIL-6R参与了多能间充质细胞向成骨细胞的分化。2)成骨分化过程中IL-6信号的激活为了了解IL-6诱导C3H10T1/2向成骨细胞分化的分子机制，我们首先检测了C3H10T1/2细胞内IL-6的信号通路。IL-6/sIL-6R使STAT1和STAT3酪氨酸磷酸化，并从胞浆移位到胞核。IL-6/sIL-6R也激活了MAP激酶。提示IL-6/sIL-6R与…伴发C3H10T1/2.3)JAK/STAT和MAP激酶信号通路在成骨细胞分化中的作用为了探讨JAK/STAT信号在成骨细胞分化中的作用，我们检测了显性负性JAK1(dN-JAK1)和JAK2(dN-JAK2)对IL-6诱导的成骨细胞分化的影响。DN-JAK1和dN-JAK2阻断了JAK/STAT信号的激活。DN-JAK1和dN-JAK2还可阻断IL-6诱导的C3H10T1/2细胞向成骨细胞分化。接下来，我们利用显性阴性ras(dN-ras)研究了MAP激酶在成骨细胞分化中的作用。DN-ras可抑制MAP激活酶的激活。结果表明，JAK/STAT信号通路及JAK/STAT信号与MAPK信号通路之间的相互作用参与了IL-6.4诱导的成骨细胞分化过程。BMP2信号调节成骨细胞分化。较少

项目成果

Gabriel Mbalaviele: "Cadherin-6 mediates the heterotypic interactions between the hemopoietic osteoclast cell lineage and stromal cells in a murine model of osteoclast differentiation"J Cell Biol. 141(6). 1467-1476 (1998)

Gabriel Mbalaviele：“在破骨细胞分化的小鼠模型中，Cadherin-6 介导造血破骨细胞谱系和基质细胞之间的异型相互作用”J Cell Biol。

Sakamuri v.Reddy: "Isolation and characterization of a cDNA clone encoding a novel peptide (OSF) that enhances osteoclast formation and bone resorption"J Cellular Physiology. 177・4. 636-645 (1998)

Sakamuri v.Reddy：“编码增强破骨细胞形成和骨吸收的新型肽（OSF）的 cDNA 克隆的分离和表征”J Cellular Physiology 177・4（1998）。

Riko Nishimura: "Combination of Interleukin-6 and Soluble Interleukin-6 Receptors induces Differentiation and Activation of JAK-STAT and MAP Kinase Pathways in MG-63 Human Osteoblastic Cells"J Bone Mineral Research. 13・5. 777-785 (1998)

Riko Nishimura：“白细胞介素 6 和可溶性白细胞介素 6 受体的组合诱导 MG-63 人成骨细胞中 JAK-STAT 和 MAP 激酶途径的分化和激活”J Bone Mineral Research 13・5。

Riko Nishimura: "Bone Morphogenetic Protein and Bone Formation"The Journal of Clinical Science. 34(19). 1378-1386 (1998)

Riko Nishimura：“骨形态发生蛋白和骨形成”临床科学杂志。

Sakamuri V.Reddy: "lsolation and Characterization of cDNA clone encoding a novel peptide (OSF) that enhances osteoclast formation and bone resorption" J cellular Physiology. 177. 636-645 (1998)

Sakamuri V.Reddy：“编码可增强破骨细胞形成和骨吸收的新型肽 (OSF) 的 cDNA 克隆的分离和表征”J 细胞生理学。