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Cell-matrix interaction in the regulation of bone metabolism and its disorder in involutional osteoporosis

细胞-基质相互作用在骨代谢调控中的作用及其在退化性骨质疏松症中的紊乱

基本信息

批准号：
11671081
负责人：
TAKEUCHI Yasuhiro
金额：
$ 2.24万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
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/grant/KAKENHI-PROJECT-11671081/
关键词：
collagen osteoblast integrin BMP DDR FAK Smad bone metastasis ERK MAPキナーゼ

项目摘要

1) Intracellular signaling activated by matrix type I collagen in osteoblastic differentiationWe have previously shown that interaction of type I collagen (COL) with α2β1 integrin is indispensable for the osteoblastic differentiation. Intracellular signaling pathways including focal adhesion kinase (FAK)- Ras-ERK have been shown to be involved in the expression of osteoblastic phenotypes. In this study, we further analyzed signals activated by COL via integrin-independent mechanism. Attachment of cells to COL stimulated tyrosine phosphorylation of discoidin domain receptor-2 (DDR2), that contains tyrosine kinase motif in its intracellular domain. Deletion of kinase region made DDR2 inactive. DDR2 might associate with FAK and phosphatidylinositol 3-kinase (PI3-K) to form a complex of signaling molecules. These signaling pathways may play an important role in the differentiation and function of osteoblasts.2) Essential corss-talk between integrin-FAK-Ras-ERK and BMP-Smad1 in osteoblastic … More differentiationWe have demonstrated that endogenous BMP-2/4 accumulated in extracellular matrices are essential for the osteoblastic differentiation of cells in the osteoblast lineage. In this study, we showed that FAK and its downstream signals were essential for Smad1 signals activated by BMP.Osteoblastic cells constitutively expressing antisense mRNA for FAK did not respond to BMP-2. Although Smad1 was phosphorylated and translocated into nuclei in response to BMP-2, Smad1-dependent transcriptional activity could not be activated in these cells. It was also demonstrated that Ras-MEK-ERK might be involved in this pathway. Therefore, FAK-Ras-ERK signals may be essential for BMP-Smad1 actions in osteoblastic cells. These results further reveal molecular mechanisms whereby cell-matrix interactions is invloved in the osteoblastic differentiation.3) Cell-cell interactions in cancer-induced osteoclastogenesisWe examined molecular mechanisms whereby cancer cells that potentially metastasize to andestruct bone induce osteoclastogenesis in vitro. Direct interactions of breast cancer Balb/c-MC or melanoma B16 cells to bone marrow cells induced RANK ligand expression to stimulate osteoclastogenesis in vitro. Thus, cell-cell interactions between cancer and bone marrow cells may be an important step of bone destruction followed by creating a focus of bone metastasis. Less

1)成骨细胞分化过程中基质I型胶原激活的细胞内信号转导我们已经证明I型胶原(Col)与α-2-β-1整合素的相互作用是成骨细胞分化所必需的。细胞内信号通路包括粘着斑激酶(FAK)-RAS-ERK已被证明参与成骨细胞表型的表达。在这项研究中，我们进一步分析了COL通过不依赖整合素的机制激活的信号。细胞与Col结合可刺激盘状结构域受体-2(DDR2)的酪氨酸磷酸化，该受体在其胞内区含有酪氨酸激酶基序。激酶区域的缺失使DDR2失活。DDR2可能与FAK和磷脂酰肌醇3-激酶(PI3-K)结合形成信号分子复合体。这些信号通路可能在成骨细胞的分化和功能中发挥重要作用。2)整合素-FAK-RAS-ERK和BMP-SMAD1在成骨细胞…中的重要相互作用更多的分化我们已经证明，内源性BMP-2/4积累在细胞外基质中，对于成骨细胞系中的细胞的成骨分化是必不可少的。在这项研究中，我们发现FAK及其下游信号是BMP激活的Smad1信号所必需的。表达FAK反义mRNA的成骨细胞对BMP-2没有反应。尽管Smad1被BMP-2磷酸化并移位到细胞核中，但这些细胞中Smad1依赖的转录活性不能被激活。Ras-MEK-ERK可能参与了这一途径。因此，FAK-RAS-ERK信号可能是BMP-Smad1在成骨细胞中发挥作用所必需的。这些结果进一步揭示了细胞-基质相互作用参与成骨细胞分化的分子机制。3)细胞-细胞相互作用在癌症诱导的破骨细胞形成中的作用我们研究了潜在转移到破坏骨的癌细胞在体外诱导破骨细胞形成的分子机制。乳腺癌Balb/c-MC或黑色素瘤B16细胞与骨髓细胞的直接相互作用诱导RANK配体的表达，从而在体外刺激破骨细胞的形成。因此，癌细胞和骨髓细胞之间的细胞间相互作用可能是骨破坏的重要一步，继而形成骨转移灶。较少