The University of Michigan, Ann Arbor, MI 48109-1078, USA.
Mol Cell Endocrinol. 2012 Nov 5;363(1-2):46-61. doi: 10.1016/j.mce.2012.07.006. Epub 2012 Jul 24.
We determined the precise role of relaxin family peptide (RXFP) receptors-1 and -2 in the regulation of MMP-9 and -13 by relaxin, and delineated the signaling cascade that contributes to relaxin's modulation of MMP-9 in fibrocartilaginous cells. Relaxin treatment of cells in which RXFP1 was silenced resulted in diminished induction of MMP-9 and -13 by relaxin, whereas overexpression of RXFP1 potentiated the relaxin-induced expression of these proteinases. Suppression or overexpression of RXFP2 resulted in no changes in the relaxin-induced MMP-9 and -13. Studies using chemical inhibitors and siRNAs to signaling molecules showed that PI3K, Akt, ERK and PKC-ζ and the transcription factors Elk-1, c-fos and, to a lesser extent, NF-κB are involved in relaxin's induction of MMP-9. Our findings provide the first characterization of signaling cascade involved in the regulation of any MMP by relaxin and offer mechanistic insights on how relaxin likely mediates extracellular matrix turnover.
我们确定了松弛素家族肽（RXFP）受体-1 和 -2 在松弛素调节 MMP-9 和 -13 中的精确作用，并描绘了导致松弛素调节纤维软骨细胞 MMP-9 的信号级联。沉默 RXFP1 的细胞中松弛素处理导致 MMP-9 和 -13 的诱导减少，而 RXFP1 的过表达增强了这些蛋白酶的松弛素诱导表达。抑制或过表达 RXFP2 不会导致松弛素诱导的 MMP-9 和 -13 发生变化。使用化学抑制剂和 siRNA 研究信号分子的研究表明，PI3K、Akt、ERK 和 PKC-ζ 以及转录因子 Elk-1、c-fos 和在较小程度上 NF-κB 参与了松弛素诱导的 MMP-9。我们的研究结果首次对松弛素调节任何 MMP 的信号级联进行了特征描述，并提供了松弛素可能介导细胞外基质周转的机制见解。
