Basic fibroblast growth factor activates the MAPK and NFκB pathways that converge on Elk-1 to control production of matrix metalloproteinase-13 by human adult articular chondrocytes
Basic fibroblast growth factor activates the MAPK and NFκB pathways that converge on Elk-1 to control production of matrix metalloproteinase-13 by human adult articular chondrocytes
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DOI：
10.1074/jbc.m706508200
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发表时间：
2007-10-26
影响因子：
4.8
通讯作者：
Im, Hee-Jeong
中科院分区：
文献类型：
--
作者：
Muddasani, Prasuna;Norman, Jim C.;Im, Hee-Jeong
关节破坏的病理与碱性成纤维细胞生长因子（bFGF）和基质金属蛋白酶-13 （MMP-13）的产生升高有关。骨性关节炎关节疾病中，软骨细胞中bFGF和MMP-13的表达及其向滑液中的释放显著增加。我们之前发现，少量暴露于bFGF会严重损害成人关节软骨细胞的软骨修复能力，因为bFGF会降低对骨形态发生蛋白-7和胰岛素样生长因子-1的反应性，并通过蛋白激酶C δ依赖性激活多种丝裂原活化蛋白激酶（MAPK）信号通路诱导MMP-13。在这里，我们使用生化和分子方法证明转录因子Elk-1是MAPK的直接下游靶点，是人关节软骨细胞中bFGF对MMP-13的关键转录激活因子。我们还提供证据表明，Elk-1是NF kappa B的直接靶点，并在NF kappa B信号通路激活后诱导MMP-13的表达。综上所述，我们的研究结果表明，MMP-13的表达升高是通过Elk-1激活MAPK和NF κ B信号通路发生的，从而揭示了bFGF控制分解代谢酶产生的双管其下的生物学机制，分解代谢酶与退行性关节疾病（如骨关节炎）中软骨基质的过度降解有关。
The pathology of joint destruction is associated with elevated production of basic fibroblast growth factor (bFGF) and matrix metalloproteinase-13 (MMP-13). In osteoarthritic joint disease, expression of bFGF and MMP-13 in chondrocytes and their release into the synovial fluid are significantly increased. We have previously found that the capacity for cartilage repair in human adult articular chondrocytes is severely compromised by minimal exposure to bFGF because bFGF reduces responsiveness to bone morphogenetic protein-7 and insulin-like growth factor-1 and induces MMP-13 through protein kinase C delta-dependent activation of multiple mitogen-activated protein kinase (MAPK) signaling pathways. Here we show using biochemical and molecular approaches that transcription factor Elk-1, a direct downstream target of MAPK, is a critical transcriptional activator of of MMP-13 by bFGF in human articular chondrocytes. We also provide evidence that Elk-1 is a direct target of NF kappa B and induces MMP-13 expression upon activation of the NF kappa B signaling pathway. Taken together, our results suggest that elevated expression of MMP-13 occurs through Elk-1 activation of both MAPK and NF kappa B signaling pathways, thus revealing a two-pronged biological mechanism by which bFGF controls the production of catabolic enzymes that are associated with excessive degradation of the cartilage matrix in degenerative joint diseases such as osteoarthritis.