Gene expression in Dupuytren's disease

Dupuytren's disease (DD) is a classic example of pathological fibrosis which results in a debilitating disorder affecting a large sector of the human population. It is characterized by excessive local proliferation of fibroblasts and over-production of collagen and other components of the extracellular matrix (ECM) in the palmar fascia. The fibrosis progressively results in contracture of elements between the palmar fascia and skin causing flexion deformity or clawing of the fingers and a severe reduction in hand function. While much is known about the pathogenesis and surgical treatment of DD, little is known about the factors that cause its onset and progression, despite many years of research. Gene expression patterns in DD patients now offers the potential to identify genes that direct the pathogenesis of DD. In this study, we used primary cultures of fibroblasts derived from excisional biopsies of fibrotic tissue from DD patients to compare the gene expression profiles on a genome-wide basis with normal control fibroblasts. Our investigations have identified genes that may be involved with DD pathogenesis including some which are directly relevant to fibrosis. In particular, these include significantly reduced expression levels of three matrix metallopeptidases (MMP1, MMP3, MMP16), follistatin, and STAT1, and significantly increased expression levels of fibroblast growth factors (FGF9, FGF11), a number of collagen genes and other ECM genes in DD patient samples. Many of these gene products are known to be involved in fibrosis, tumour formation and in the normal processes of tissue remodelling. In addition, alternative splicing was identified in some DD-associated genes. These highly sensitive genomic investigations provide new insight into the molecular mechanisms that may underpin the development and progression of DD. Four exon arrays of DD primary fibroblasts derived from fibrotic tissue were compared to fibroblasts derived from skin punch biopsies from individuals who did not show DD symptoms.

杜普伊特伦挛缩症（Dupuytren's disease, DD）是病理性纤维化的典型范例，可引发致残性病症，影响全球大量人群。该病以掌腱膜部位成纤维细胞过度局部增殖、胶原蛋白及细胞外基质（extracellular matrix, ECM）其他组分过量产生为特征。此种纤维化会逐渐引发掌腱膜与皮肤间组织的挛缩，进而导致手指屈曲畸形或爪形手，严重损害手部功能。尽管历经多年研究，学界对杜普伊特伦挛缩症的发病机制与外科治疗已有较多认知，但对其诱因及病程进展的相关因素仍知之甚少。如今，杜普伊特伦挛缩症患者的基因表达谱有望助力识别调控该病发病机制的相关基因。本研究采用杜普伊特伦挛缩症患者纤维化组织切除活检标本所培养的原代成纤维细胞，在全基因组范围内与正常对照成纤维细胞进行基因表达谱对比分析。本研究已筛选出可能参与杜普伊特伦挛缩症发病机制的基因，其中部分与纤维化进程直接相关。具体而言，杜普伊特伦挛缩症患者样本中，三种基质金属蛋白酶（matrix metallopeptidases, MMP1、MMP3、MMP16）、卵泡抑素（follistatin）以及STAT1的表达水平显著下调，而成纤维细胞生长因子（fibroblast growth factors, FGF9、FGF11）、多个胶原蛋白基因及其他细胞外基质基因的表达水平则显著上调。上述多数基因产物已被证实与纤维化、肿瘤发生及正常组织重塑过程相关。此外，本研究还在部分杜普伊特伦挛缩症相关基因中发现了可变剪接现象。此项高灵敏度的基因组研究为阐明杜普伊特伦挛缩症发生与进展的分子机制提供了全新视角。本研究将4组源自纤维化组织的杜普伊特伦挛缩症患者原代成纤维细胞的外显子芯片（exon array）数据，与来自无杜普伊特伦挛缩症症状个体皮肤穿刺活检标本的成纤维细胞进行对比分析。