Uitto V J, Airola K, Vaalamo M, Johansson N, Putnins E E, Firth J D, Salonen J, López-Otín C, Saarialho-Kere U, Kähäri V M
Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, Canada.
Am J Pathol. 1998 Jun;152(6):1489-99.
Increased proliferation of mucosal epithelium during inflammation is associated with degradation of subepithelial connective tissue matrix and local invasion of the epithelial cells. Here we have studied, whether collagenase-3 (MMP-13), a collagenolytic matrix metalloproteinase with an exceptionally wide substrate specificity, is expressed in the epithelium of chronically inflamed mucosa. Examination of human gingival tissue sections from subjects with chronic adult periodontitis with in situ hybridization revealed marked expression of MMP-13 in basal cells of some epithelial rete ridges expanding into connective tissue. Immunohistochemical staining demonstrated that these cells also expressed strongly laminin-5, suggesting that they are actively migrating cells. A strong signal for MMP-13 mRNA was occasionally also noted in the suprabasal epithelial cells facing the gingival pocket, whereas no collagenase-1 (MMP-1) mRNA was detected in any areas of the epithelium. MMP-13 expression was also detected in fibroblast-like cells associated with collagen fibers of the inflamed subepithelial connective tissue. In organ culture of human oral mucosa, MMP-13 mRNA expression was observed in epithelial cells growing into connective tissue of the specimens. Regulation of MMP-13 expression was examined in cultured normal nonkeratinizing epithelial cells isolated from porcine periodontal ligament. In these cells, MMP-13 expression at the mRNA and protein level was potently enhanced (up to sixfold) by tumor necrosis factor-alpha, transforming growth factor-beta(1), and transforming growth factor-alpha and by keratinocyte growth factor in the presence of heparin. In addition, plating periodontal ligament epithelial cells on type I collagen stimulated MMP-13 expression (sevenfold) as compared with cells grown on tissue culture plastic. The results of this study show, that expression of MMP-13 is specifically induced in undifferentiated epithelial cells during chronic inflammation due to exposure to cytokines and collagen. Thus, it is likely that MMP-13 expression is instrumental in the subepithelial collagenolysis and local invasion of the activated mucosal epithelium into the connective tissue.
炎症期间黏膜上皮细胞增殖增加与上皮下结缔组织基质降解及上皮细胞局部浸润有关。在此，我们研究了具有异常广泛底物特异性的胶原酶-3（MMP-13），一种胶原溶解基质金属蛋白酶，是否在慢性炎症黏膜的上皮中表达。用原位杂交法检测慢性成人牙周炎患者的人牙龈组织切片，发现MMP-13在一些延伸至结缔组织的上皮嵴的基底细胞中有明显表达。免疫组织化学染色表明，这些细胞也强烈表达层粘连蛋白-5，提示它们是活跃迁移的细胞。在面向牙龈袋的基底上层上皮细胞中偶尔也可检测到MMP-13 mRNA的强信号，而在上皮的任何区域均未检测到胶原酶-1（MMP-1）mRNA。在与炎症上皮下结缔组织的胶原纤维相关的成纤维样细胞中也检测到MMP-13表达。在人口腔黏膜器官培养中，在生长至标本结缔组织中的上皮细胞中观察到MMP-13 mRNA表达。在从猪牙周韧带分离的培养正常非角质化上皮细胞中检测MMP-13表达的调节。在这些细胞中，肿瘤坏死因子-α、转化生长因子-β(1)、转化生长因子-α以及在肝素存在下的角质形成细胞生长因子可显著增强（高达六倍）MMP-13在mRNA和蛋白水平的表达。此外，与在组织培养塑料上生长的细胞相比，将牙周韧带上皮细胞接种在I型胶原上可刺激MMP-13表达（七倍）。本研究结果表明，在慢性炎症期间，由于暴露于细胞因子和胶原，MMP-13在未分化上皮细胞中特异性诱导表达。因此，MMP-13表达可能在上皮下胶原溶解以及活化的黏膜上皮向结缔组织的局部浸润中起作用。
