Increased KGF Expression Promotes Fibroblast Activation in a Double Paracrine Manner Resulting in Cutaneous Fibrosis
Increased KGF Expression Promotes Fibroblast Activation in a Double Paracrine Manner Resulting in Cutaneous Fibrosis
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DOI：
10.1038/jid.2012.389
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发表时间：
2013-03-01
影响因子：
6.5
通讯作者：
Bosserhoff, Anja K.
中科院分区：
文献类型：
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作者：
Canady, Johanna;Arndt, Stephanie;Bosserhoff, Anja K.
皮肤纤维化疾病的共同特征是活化成纤维细胞增加细胞外基质成分的产生和沉积。它们的临床病程范围从局部皮肤受累的良性到危及生命的全身性疾病。成纤维细胞活化的分子原因尚不清楚，但上皮-间充质相互作用在纤维发生的研究领域引起了越来越多的关注。我们检测了角质细胞生长因子（KGF），这是成纤维细胞-角质细胞串音的关键分子，例如在瘢痕疙瘩和硬皮病中，发现与健康对照相比，其在疾病来源的成纤维细胞和组织中的表达增加。这种过表达通过双旁分泌模式诱导成纤维细胞激活。在KGF刺激下，角质形成细胞产生并分泌OSM（抑癌素M）。OSM反过来激活成纤维细胞，与成纤维细胞激活蛋白1- α 1型胶原的表达增加和迁移增强反应。观察到的胶原表达和成纤维细胞迁移的增加可以追溯到osm调节的STAT3磷酸化，导致尿激酶纤溶酶原激活物表达增强。因此，我们提出了一种由间充质细胞中KGF的过度表达介导的皮肤纤维化疾病发病机制的致病环。Journal of Investigative Dermatology (2013) 133, 647-657；doi: 10.1038 / jid.2012.389;2012年10月25日在线发布
Fibrotic disorders of the skin share the characteristic features of increased production and deposition of extracellular matrix components by activated fibroblasts. Their clinical course ranges from benign with localized cutaneous involvement to a systemic, life-threatening disease. The molecular cause for fibroblast activation remains unknown, yet epithelial-mesenchymal interactions draw mounting attention in the research field of fibrogenesis. We examined keratinocyte growth factor (KGF), a crucial molecule in fibroblast-keratinocyte cross talk, exemplarily in keloid and scleroderma, and found its expression to be increased in disease-derived fibroblasts and tissues compared with healthy controls. This overexpression induces fibroblast activation through a double paracrine mode of action. Upon KGF stimulation, the keratinocytes produced and secreted OSM (oncostatin M). Fibroblasts were in turn activated by OSM reacting with the increased expression of collagen type 1-alpha 1, fibroblast activation protein, and enhanced migration. The observed increase in collagen expression and fibroblast migration can be traced back to OSM-regulated STAT3 phosphorylation, leading to enhanced urokinase plasminogen activator expression. Hence, we propose a causative loop in the pathogenesis of fibrosing disorders of the skin mediated by the overexpression of KGF in mesenchymal cells. Journal of Investigative Dermatology (2013) 133, 647-657; doi:10.1038/jid.2012.389; published online 25 October 2012