IL-1 induces collagenase-3 (MMP-13) promoter activity in stably transfected chondrocytic cells: requirement for Runx-2 and activation by p38 MAPK and JNK pathways
IL-1 induces collagenase-3 (MMP-13) promoter activity in stably transfected chondrocytic cells: requirement for Runx-2 and activation by p38 MAPK and JNK pathways
复制标题
DOI：
10.1093/nar/29.21.4361
复制
发表时间：
2001-11-01
影响因子：
14.9
通讯作者：
Brinckerhoff, CE
中科院分区：
文献类型：
--
作者：
Mengshol, JA;Vincenti, MP;Brinckerhoff, CE
骨关节炎软骨细胞响应白细胞介素 1 (IL-1) 分泌基质金属蛋白酶 13 (MMP-13)，导致软骨中 II 型胶原蛋白的消化。使用软骨细胞，我们之前确定 IL-1 诱导强烈的 MMP-13 转录反应，该反应需要 p38 MAPK、JNK 和转录因子 NF-kappaB。现在，我们研究了MMP-13的组织特异性转录调控。转录因子 Runx-2 的组成型表达与细胞类型表达 MMP-13 的能力相关，并且是 IL-1 诱导所需的；此外，Runx-2 通过与 p38 MAPK 信号通路协同增强 IL-1 对 MMP-13 转录的诱导。瞬时转染的 MMP-13 启动子不是 IL-1 诱导型的。然而，稳定整合的启动子的-405 bp足以使IL-1诱导5至6倍的报告基因活性，并且该整合的报告基因需要与内源基因相同的p38 MAPK途径。最后，近端 Runx 结合位点和近端 AP-1 位点的突变削弱了对 IL-1 的转录反应，并且双突变协同降低了报告基因活性。总之，我们的数据表明，MMP-13 对 IL-1 的转录反应是由 p38 途径控制的，p38 途径通过组织特异性转录因子 Runx-2 和普遍存在的 AP-1 转录因子在 MMP-13 启动子上相互作用。
Osteoarthritic chondrocytes secrete matrix metalloproteinase-13 (MMP-13) in response to interleukin-1 (IL-1), causing digestion of type II collagen in cartilage. Using chondrocytic cells, we previously determined that IL-1 induced a strong MMP-13 transcriptional response that requires p38 MAPK, JNK and the transcription factor NF-kappaB. Now, we have studied the tissue-specific transcriptional regulation of MMP-13. Constitutive expression of the transcription factor Runx-2 correlated with the ability of a cell type to express MMP-13 and was required for IL-1 induction; moreover, Runx-2 enhanced IL-1 induction of MMP-13 transcription by synergizing with the p38 MAPK signaling pathway. Transiently transfected MMP-13 promoters were not IL-1 inducible. However, -405 bp of stably integrated promoter was sufficient for 5- to 6-fold IL-1 induction of reporter activity and this integrated reporter required the same p38 MAPK pathway as the endogenous gene. Finally, mutation of the proximal Runx binding site and the proximal AP-1 site blunted the transcriptional response to IL-1, and double mutation synergistically decreased reporter activity. In summary, our data suggest that the transcriptional MMP-13 response to IL-1 is controlled by the p38 pathway interacting at the MMP-13 promoter through the tissue-specific transcription factor Runx-2 and the ubiquitous AP-1 transcription factor.