Interleukin-1 induction of collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c-Jun N-terminal kinase, and nuclear factor κB -: Differential regulation of collagenase 1 and collagenase 3
Interleukin-1 induction of collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c-Jun N-terminal kinase, and nuclear factor κB -: Differential regulation of collagenase 1 and collagenase 3
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DOI：
10.1002/1529-0131(200004)43:4
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发表时间：
2000-04-01
影响因子：
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通讯作者：
Brinckerhoff, CE
中科院分区：
文献类型：
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作者：
Mengshol, JA;Vincenti, MP;Brinckerhoff, CE
Objective.研究白细胞介素-1（IL-1）诱导软骨细胞胶原酶3（基质金属蛋白酶13 [MMP-13]）基因表达的机制，以更好地理解该基因在这些细胞中是如何被诱导的，以及它如何促进骨关节炎中软骨的降解。首先评估MMP-13基因对IL-1的转录和转录后应答。然后，用丝裂原活化蛋白激酶（MAPK）信号通路的直接抑制剂和核因子κ B（NF-κ B B）的组成性阻遏物来评估各个通路在IL-1介导的MMP-13诱导中的作用。我们发现IL-1诱导MMP-13需要p38活性、c-Jun N-末端激酶（JNK）活性和NF-κ B易位。这些结果表明，NF-κ B和激活蛋白1转录因子是必需的IL-1诱导MMP-13。我们还比较了IL-1刺激关节软骨细胞和软骨肉瘤细胞中胶原酶1（MMP-1）所需的信号通路，发现IL-1诱导MMP-1需要与MMP-13所需的不同通路。在软骨肉瘤细胞中，MMP-1的诱导依赖于p38和MEK（细胞外信号调节激酶途径的MAPK激酶），而不需要JNK或NF-κ B。在关节软骨细胞中，抑制MEK没有效果，而抑制p38则产生不同的结果。这些研究首次证明，p38、JNK和NF-κ B是IL-1诱导MMP-13所必需的。结果还突出了MMP-1和MMP-13诱导中对信号通路的不同要求。此外，他们证明了软骨细胞中IL-1对MMP-1的诱导依赖于细胞类型特异性的信号传导途径的独特组合。
Objective. To examine the mechanism of interleukin-1 (IL-1)-induced collagenase 3 (matrix metalloproteinase 13 [MMP-13]) gene expression in cultured chondrocytes for the purpose of better understanding how the gene is induced in these cells, and how it contributes to cartilage degradation in osteoarthritis.Methods. The transcriptional and posttranscriptional responses of the MMP-13 gene to IL-1 were assessed first. Then, direct inhibitors of mitogen-activated protein kinase (MAPK) signaling pathways and a constitutive repressor of nuclear factor kappa B (NF-kappa B) were used to assess the role of each pathway in IL-1-mediated induction of MMP-13.Results. We found that IL-1 induction of MMP-13 requires p38 activity, c-Jun N-terminal kinase (JNK) activity and NF-kappa B translocation. These results suggest that both NF-kappa B and activator protein 1 transcription factors are necessary for IL-1 induction of MMP-13. We also compared the signaling pathways necessary for IL-1 to stimulate collagenase 1 (MMP-1) in articular chondrocytes and chondrosarcoma cells and found that IL-1 induction of MMP-1 requires different pathways from those required by MMP-13. In chondrosarcoma cells, MMP-1 induction depends on p38 and MEK (an MAPK kinase of the extracellular signal-regulated kinase pathway) and does not require JNK or NF-kappa B. In articular chondrocytes, inhibition of MEK had no effect, while inhibition of p38 gave variable results.Conclusion. These studies demonstrate, for the first time, that p38, JNK, and NF-kappa B are required for IL-1 induction of MMP-13. The results also highlight the differential requirements for signaling pathways in the induction of MMP-1 and MMP-13. Additionally, they demonstrate that induction of MMP-1 by IL-1 in chondrocytic cells depends on unique combinations of signaling pathways that are cell type-specific.