Aden N, Shiwen X, Aden D, Black C, Nuttall A, Denton C P, Leask A, Abraham D, Stratton R
Centre for Rheumatology, Royal Free Hospital and University College School of Medicine, Royal Free Campus, Rowland Hill Street, London NW3 2QG, UK.
Rheumatology (Oxford). 2008 Dec;47(12):1754-60. doi: 10.1093/rheumatology/ken370. Epub 2008 Oct 1.
To identify using proteomic analysis, proteins of altered abundance in the skin of patients with SSc.
4 mm excision biopsies were obtained from the forearm involved skin of 12 diffuse SSc patients and 12 healthy controls. Two-dimensional gel electrophoresis was used to separate and define proteins in normal and SSc skin biopsy material. Proteins of altered abundance in the disease were formally identified by mass spectroscopy. Abnormalities of the epidermis were confirmed by immunohistochemistry.
Proteomic analysis revealed altered abundance of proteins involved in extracellular matrix production, myofibroblast contractility, energy metabolism and response to oxidative stress. In addition, proteins specific to the epidermis and involved in epidermal cell differentiation were altered in abundance in the disease. SSc epidermis is thickened, has an expanded nucleated cell layer, and exhibits abnormal persistence of basal marker keratin 14, delayed expression of maturation markers keratin 1/10 and the induction of keratins 6 and 16, normally absent from interfollicular skin and induced following epidermal injury. These changes closely resemble the activated phenotype seen during wound healing.
Consistent with previous models of SSc pathogenesis these data are showing increased contractility, increased extracellular matrix and response to oxidative stress in the involved skin of recent onset SSc patients. In addition, we show that SSc epidermis has an activated, wound healing phenotype. These findings are important because epidermal cells activated by injury induce and regulate local fibroblasts during wound repair.
通过蛋白质组学分析，鉴定系统性硬化症（SSc）患者皮肤中丰度改变的蛋白质。
从12例弥漫性SSc患者和12例健康对照者受累的前臂皮肤获取4毫米切除活检组织。采用二维凝胶电泳分离并鉴定正常和SSc皮肤活检材料中的蛋白质。通过质谱正式鉴定疾病中丰度改变的蛋白质。通过免疫组织化学确认表皮异常。
蛋白质组学分析显示，参与细胞外基质产生、肌成纤维细胞收缩、能量代谢和氧化应激反应的蛋白质丰度发生改变。此外，疾病中表皮特异性且参与表皮细胞分化的蛋白质丰度也发生了改变。SSc表皮增厚，有核细胞层扩大，基底标志物角蛋白14异常持续存在，成熟标志物角蛋白1/10表达延迟，角蛋白6和16被诱导表达，而在毛囊间皮肤中通常不存在这些角蛋白，它们在表皮损伤后被诱导表达。这些变化与伤口愈合过程中出现的活化表型非常相似。
与先前的SSc发病机制模型一致，这些数据表明近期发病的SSc患者受累皮肤的收缩性增加、细胞外基质增加以及对氧化应激的反应增加。此外，我们表明SSc表皮具有活化的伤口愈合表型。这些发现很重要，因为损伤激活的表皮细胞在伤口修复过程中诱导并调节局部成纤维细胞。
