Pannu Jaspreet, Trojanowska Maria
Division of Rheumatology and Immunology, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA.
Curr Opin Rheumatol. 2004 Nov;16(6):739-45. doi: 10.1097/01.bor.0000137894.63091.1a.
Systemic sclerosis is a complex disease manifesting itself by fibrosis of skin and other internal organs. Fibroblasts isolated from scleroderma lesions and cultured in vitro are characterized by increased synthesis of collagen and other extracellular matrix proteins, consistent with the disease phenotype. Cultured systemic sclerosis fibroblasts therefore serve as a principal experimental model for studying the molecular and cellular mechanisms involved in collagen overproduction in this disease. This review will discuss recent findings related to intracellular signal transduction pathways implicated in deregulated extracellular matrix deposition by systemic sclerosis fibroblasts.
Recent findings suggest that constitutively elevated synthesis of extracellular matrix by cultured systemic sclerosis fibroblasts is, at least in part, due to the aberrant activation of the autocrine transforming growth factor-beta signaling. Enhanced constitutive transforming growth factor-beta signaling may result from the elevated levels of transforming growth factor-beta receptor type I and/or inappropriate activation of Smad3. These alterations of the transforming growth factor-beta signaling in systemic sclerosis fibroblasts may facilitate increased collagen production in vivo even under conditions of low ligand availability. However, there exist many inconsistencies among published reports regarding the detailed mechanisms of this pathway in systemic sclerosis fibroblasts, and additional studies in this area are needed. Other signaling molecules implicated in fibrotic phenotype include several members of the protein kinase C family, mammalian target of rapamycin, mitogen-activated protein kinase, necdin, reactive oxygen species, and sphingolipids. These signaling pathways may work in conjunction with transforming growth factor-beta signaling to regulate the behavior of systemic sclerosis fibroblasts.
Alterations in multiple signaling pathways contribute to elevated extracellular matrix synthesis by systemic sclerosis fibroblasts. Improved understanding of the key signaling molecules may provide a novel avenue for therapeutic interventions.
系统性硬化症是一种复杂疾病，表现为皮肤和其他内脏器官的纤维化。从硬皮病病变中分离并在体外培养的成纤维细胞，其特征是胶原蛋白和其他细胞外基质蛋白的合成增加，这与疾病表型一致。因此，培养的系统性硬化症成纤维细胞是研究该疾病中胶原蛋白过度产生所涉及的分子和细胞机制的主要实验模型。本综述将讨论与系统性硬化症成纤维细胞中细胞内信号转导途径相关的最新发现，这些途径与细胞外基质沉积失调有关。
最新研究结果表明，培养的系统性硬化症成纤维细胞中细胞外基质的持续合成增加，至少部分是由于自分泌转化生长因子-β信号的异常激活。持续增强的转化生长因子-β信号可能源于I型转化生长因子-β受体水平的升高和/或Smad3的不适当激活。系统性硬化症成纤维细胞中转化生长因子-β信号的这些改变，即使在配体可用性较低的情况下，也可能促进体内胶原蛋白生成的增加。然而，关于该途径在系统性硬化症成纤维细胞中的详细机制，已发表的报告存在许多不一致之处，该领域还需要更多研究。其他与纤维化表型相关的信号分子包括蛋白激酶C家族的几个成员、雷帕霉素哺乳动物靶点、丝裂原活化蛋白激酶、神经生长抑制因子、活性氧和鞘脂。这些信号通路可能与转化生长因子-β信号协同作用，以调节系统性硬化症成纤维细胞的行为。
多种信号通路的改变导致系统性硬化症成纤维细胞的细胞外基质合成增加。更好地理解关键信号分子可能为治疗干预提供新途径。
