Roles of Matrix Metalloproteinases in wound healing and neovascuarization

皮肤创面的愈合依赖于细胞迁移和细胞外基质重塑。这两个过程都是重新上皮化和修复结缔组织所必需的，被认为涉及细胞外蛋白水解酶的作用。我们对文库进行了筛选，发现6个基质金属蛋白酶基因在大鼠皮肤创伤愈合过程中高表达，明胶酶A(Gela)和膜型1基质金属蛋白酶(MT1-MMP)转录本在基质细胞中表达。在肉芽组织中检测到高水平的成熟Gela形式，而在再生的表皮中检测不到，提示MT1-MMPs和Gela在大鼠皮肤创面愈合过程中有助于结缔组织的修复和新生血管的形成。此外，我们还利用琼脂糖珠模型证明了TIMP-2是MT1-MMP激活前Gela所必需的。我们现在制作了MT1-基质金属蛋白酶基因敲除小鼠。我们已经获得了Gela基因敲除小鼠，并正在研究正常小鼠和Gela基因敲除小鼠在伤口愈合和新生血管过程中的差异。我们还研究了合成的基质金属蛋白酶抑制剂对创面愈合过程和/或新生血管的影响。

Skin wound healing depends on cell migration and extracellular matrix remodeling. Both processes, which are necessary for reepithelization and restoration of the underlying connective tissue, are believed to involve the action of extracellular proteinases. We screened cDNA libraries and found that six matrix metalloproteinase genes were highly expressed during rat skin wound healing.GelatinaseA (GelA) and membrane-type 1 matrix metalloproteinase (MT1-MMP) transcripts were expressed in stromal cells. The detection of high levels of the mature GelA form in the granulation tissue but not in the regenerating epidermis, suggest that MT1-MMP and GelA contribute to the restoration of connective tissue and neovascularization during rat skin wound healing. Furthermore, we showed that TIMP-2 is necessary for activation of pro-GelA by MT1-MMP using agarose beads model. We now make knock-out mice of MT1-MMP gene. Already we have obtained GelA knock-out mice, and we are under studying on the differences of wound healing and neovascular process between normal mice and knock-out mice. We also study on the effect of synthetic MMP inhibitor to wound healing process and/or neovascularization.