中國醫藥大學機構典藏 China Medical University Repository, Taiwan:Item 310903500/711
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    题名: 探討SDF-1刺激對軟骨細胞分泌細胞間質水解酵素之作用;Stromal cell-derived factor-1 induces matrix metalloprotease-13 expression in human chondrocytes
    作者: 邱詠証;Yung-Cheng Chiu
    贡献者: 中國醫藥大學：臨床醫學研究所碩士班
    关键词: 細胞間質水解酵素;人類軟骨細胞;SDF-1;MMP- 13
    日期: 2008-07-02
    上传时间: 2009-08-12 14:23:39 (UTC+8)
    摘要: Stromal cell-derived factor-1(SDF-1)在退化性關節炎及風濕性關節炎病患的關節液中皆可以發現其含量顯著的提高。細胞間質水解酵素(Matrix metalloproteinases; MMP)則早已被證實會破壞關節軟骨導致關節炎的發生。但是到底經由何種訊息傳導路徑來調控人類軟骨細胞分泌MMP-13，則尚未有定論。在本論文中，我們經由RT-PCR，Western blot及Zymography發現SDF-1會誘導人類軟骨細胞分泌MMP- 13。SDF-1也會促使它在人類軟骨細胞上的接受器CXCR4提高表現量。相對的，CXCR4抗體(neutralizing antibody)，CXCR4化學抑制劑(AMD3100)及CXCR4 si-RNA則會抑制SDF-1誘導人類軟骨細胞分泌MMP-13的表現。此外，SDF-1誘導人類軟骨細胞分泌MMP-13的表現是經由磷酸化ERK訊息傳導路徑及增加轉錄因子c-Fos及c-Jun的表現來啟動MMP-13驅動子(promotor)的活力。轉錄因子c-Fos及c-Jun結合到MMP-13驅動子(promotor)上AP-1序列從而增加MMP-13的表現可以由將人類軟骨細胞轉殖帶有MMP-13驅動子的質體(luciferase plasmid)再給予SDF-1的刺激來證明。相對的，將人類軟骨細胞轉殖dominant -negative mutant of ERK(DN-ERK)或antisense c-Fos(AS c-Fos)及antisense c-Jun(AS c-Jun)則會抑制SDF-1誘導人類軟骨細胞分泌MMP-13的表現。此抑制效果也可由冷光偵測儀上的表現得知。綜合以上實驗結果，我們發現SDF-1可以經由人類軟骨細胞接受器CXCR4，接著磷酸化ERK訊息傳導路徑並活化轉錄因子c-Fos及c-Jun結合到MMP-13驅動子(promotor)上AP-1序列，最後誘導人類軟骨細胞分泌MMP-13破壞軟骨導致關節炎的產生。

    The production of chemokine stromal cell-derived factor(SDF)-1 is significantly higher in synovial fluid of patients with osteoarthritis and rheumatoid arthritis. Matrix metalloproteinase (MMP)-13 may contribute to the breakdown of articular cartilage during arthritis.
    Here, we found that SDF-1α increased the secretion of MMP-13 in cultured human chondrocytes, as shown by reverse transcriptase-polymerase chain reaction, Western blot, and zymographic analysis. SDF-1α also increased the surface expression of CXCR4 receptor in human chondrocytes. CXCR4-neutralizing antibody, CXCR4-specific inhibitor[1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl) phenyl]methyl]-1,4,8,11-tetrazacyclotetradecane (AMD3100)], orsmall interfering RNA against CXCR4 inhibited the SDF-1α-induced increase of MMP-13 expression.
    The transcriptional regulation of MMP-13 by SDF-1α was mediated by phosphorylation of extracellular signal-regulated kinases (ERK) and activation of the activator protein (AP)-1 components of c-Fos and c-Jun. The binding of c-Fos and c-Jun to the activator protein(AP-1) element on the MMP-13 promoter and the increase in luciferase activity was enhanced by SDF-1α. Cotransfection with dominant-negative mutant of ERK2 or c-Fos and c-Jun antisense oligonucleotide inhibited the potentiating action of SDF-1α on MMP-13 promoter activity.
    Taken together, our results provide evidence that SDF-1α acts through CXCR4 to activate ERK and the downstream transcription factors (c-Fos and c-Jun), resulting in the activation of AP-1 on the MMP-13 promoter and contributing cartilage destruction during arthritis.
    显示于类别:[臨床醫學研究所] 博碩士論文

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