TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin
TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin
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DOI：
10.1073/pnas.1416181112
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发表时间：
2015-02-03
影响因子：
11.1
通讯作者：
Orioli, Donata
中科院分区：
文献类型：
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作者：
Arseni, Lavinia;Lanzafame, Manuela;Orioli, Donata
DNA 修复/转录因子 TFIIH 的 XPD 亚基突变会导致不同的临床症状，包括易患癌症的着色性干皮病 (XP) 和多系统疾病毛发硫营养不良 (TTD)，它们仅具有皮肤光敏性。原代真皮成纤维细胞的基因表达谱显示，与健康父母相比，XPD 突变的 TTD 患者中基质金属蛋白酶 1 (MMP-1) 过度表达，该基因编码可降解细胞外基质 (ECM) 间质胶原的金属蛋白酶。这种缺陷是在 TTD 中观察到的，而不是在 XP 中观察到的，并且是成纤维细胞特有的，而成纤维细胞是真皮 ECM 的主要产生者。 TTD 中的 MMP-1 转录上调是由 MMP-1 启动子上的视黄酸受体介导的错误信号引起的，并导致细胞/组织系统和 TTD 患者皮肤的 ECM 中活性 MMP-1 酶的过度分泌和 I 型胶原蛋白的降解。与 ECM 在引发控制细胞行为和组织稳态的信号事件中众所周知的作用一致，TTD 中 ECM 的改变被证明会影响患者真皮成纤维细胞的迁移和伤口愈合特性。 MMP 活性的特异性抑制剂的存在足以恢复正常的细胞迁移，从而为治疗策略提供了一种潜在的方法。这项研究强调了 ECM 异常与 TTD 发病机制以及 TTD 和 XP 之间表型差异的相关性。
Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH result in distinct clinical entities, including the cancer-prone xeroderma pigmentosum (XP) and the multisystem disorder trichothiodystrophy (TTD), which share only cutaneous photosensitivity. Gene-expression profiles of primary dermal fibroblasts revealed overexpression of matrix metalloproteinase 1 (MMP-1), the gene encoding the metalloproteinase that degrades the interstitial collagens of the extracellular matrix (ECM), in TTD patients mutated in XPD compared with their healthy parents. The defect is observed in TTD and not in XP and is specific for fibroblasts, which are the main producers of dermal ECM. MMP-1 transcriptional up-regulation in TTD is caused by an erroneous signaling mediated by retinoic acid receptors on the MMP-1 promoter and leads to hypersecretion of active MMP-1 enzyme and degradation of collagen type I in the ECM of cell/tissue systems and TTD patient skin. In agreement with the well-known role of ECM in eliciting signaling events controlling cell behavior and tissue homeostasis, ECM alterations in TTD were shown to impact on the migration and wound-healing properties of patient dermal fibroblasts. The presence of a specific inhibitor of MMP activity was sufficient to restore normal cell migration, thus providing a potential approach for therapeutic strategies. This study highlights the relevance of ECM anomalies in TTD pathogenesis and in the phenotypic differences between TTD and XP.