Johnston Phillip, Chojnowski Adrian J, Davidson Rose K, Riley Graham P, Donell Simon T, Clark Ian M
Institute of Orthopaedics, Norfolk and Norwich University Hospital, Norwich, UK.
J Hand Surg Am. 2007 Mar;32(3):343-51. doi: 10.1016/j.jhsa.2006.12.010.
Dupuytren's disease (DD) is a common fibrotic condition of the palmar fascia, leading to deposition of collagen-rich cords and finger contractions. The metzincin superfamily contains key enzymes in the turnover of collagen and other extracellular matrix macromolecules. A number of broad-spectrum matrix metalloproteinase inhibitors, used in cancer clinical trials, caused side effects of DD-like contractures. We tested the hypothesis that changes in the expression of specific metalloproteinases underlie or contribute to the fibrosis and contracture seen in DD.
We collected tissue from patients with DD and used normal palmar fascia as a control. We profiled the expression of the entire matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinases (TIMP), and a disintegrin and metalloproteinase domain with thrombospondin motif (ADAMTS) gene families in these tissues using real-time reverse-transcription polymerase chain reaction.
A number of metalloproteinases and inhibitors are regulated in DD. The expression of 3 key collagenases, MMP1, MMP13, and MMP14 is increased significantly in the DD nodule, as is the expression of the collagen biosynthetic enzyme ADAMTS14. The expression of MMP7, an enzyme with broad substrate specificity, is increased in the DD nodule and remains equally expressed in the DD cord. TIMP1 expression is increased significantly in DD nodule compared with normal palmar fascia.
This study measured the expression of all MMP, ADAMTS, and TIMP genes in DD. Contraction and fibrosis may result from: (1) increased collagen biosynthesis mediated by increased ADAMTS-14; (2) an increased level of TIMP-1 blocking MMP-1- and MMP-13-mediated collagenolysis; and (3) contraction enabled by MMP-14-mediated pericellular collagenolysis (and potentially MMP-7), which may escape inhibition by TIMP-1. The complete expression profile will provide a knowledge-based approach to novel therapeutics targeting these genes.
杜普伊特伦挛缩症（DD）是一种常见的掌腱膜纤维化疾病，会导致富含胶原蛋白的条索状组织沉积以及手指挛缩。金属蛋白酶超家族包含胶原蛋白和其他细胞外基质大分子周转过程中的关键酶。一些用于癌症临床试验的广谱基质金属蛋白酶抑制剂会引发类似DD挛缩的副作用。我们检验了这样一个假说，即特定金属蛋白酶表达的变化是DD中所见纤维化和挛缩的基础或促成因素。
我们收集了DD患者的组织，并使用正常掌腱膜作为对照。我们通过实时逆转录聚合酶链反应分析了这些组织中整个基质金属蛋白酶（MMP）、金属蛋白酶组织抑制剂（TIMP）以及含血小板反应蛋白基序的解整合素和金属蛋白酶结构域（ADAMTS）基因家族的表达情况。
DD中多种金属蛋白酶和抑制剂受到调控。3种关键胶原酶MMP1、MMP13和MMP14在DD结节中的表达显著增加，胶原蛋白生物合成酶ADAMTS14的表达也是如此。MMP7是一种具有广泛底物特异性的酶，其在DD结节中的表达增加，在DD条索中表达水平保持不变。与正常掌腱膜相比，TIMP1在DD结节中的表达显著增加。
本研究测定了DD中所有MMP、ADAMTS和TIMP基因的表达。挛缩和纤维化可能源于：（1）ADAMTS - 14增加介导的胶原蛋白生物合成增加；（2）TIMP - 1水平升高阻断了MMP - 1和MMP - 13介导的胶原溶解；（3）MMP - 14介导的细胞周围胶原溶解（可能还有MMP - 7）促成挛缩，这可能逃避TIMP - 1的抑制。完整的表达谱将为针对这些基因的新型治疗方法提供基于知识的途径。
