鉴定钙黏蛋白 11 为皮肤纤维化的介质及在系统性硬皮病中的可能作用。
Identification of cadherin 11 as a mediator of dermal fibrosis and possible role in systemic sclerosis.
机构信息
University of Texas Health Science Center at, Houston.
出版信息
Arthritis Rheumatol. 2014 Apr;66(4):1010-21. doi: 10.1002/art.38275.
OBJECTIVE
Systemic sclerosis (SSc) is a chronic autoimmune disease clinically manifesting as progressive fibrosis of the skin and internal organs. Recent microarray studies demonstrated that cadherin 11 (Cad-11) expression is increased in the affected skin of patients with SSc. The purpose of this study was to examine our hypothesis that Cad-11 is a mediator of dermal fibrosis.
METHODS
Biopsy samples of skin from SSc patients and healthy control subjects were used for real-time quantitative polymerase chain reaction analysis to assess Cad-11 expression and for immunohistochemistry to determine the expression pattern of Cad-11. To determine whether Cad-11 is a mediator of dermal fibrosis, Cad-11-deficient mice and anti-Cad-11 monoclonal antibodies (mAb) were used in the bleomycin-induced dermal fibrosis model. In vitro studies with dermal fibroblasts and bone marrow-derived macrophages were used to determine the mechanisms by which Cad-11 contributes to the development of tissue fibrosis.
RESULTS
Levels of messenger RNA for Cad-11 were increased in skin biopsy samples from patients with SSc and correlated with the modified Rodnan skin thickness scores. Cad-11 expression was localized to dermal fibroblasts and macrophages in SSc skin. Cad-11-knockout mice injected with bleomycin had markedly attenuated dermal fibrosis, as quantified by measurements of skin thickness, collagen levels, myofibroblast accumulation, and profibrotic gene expression, in lesional skin as compared to the skin of wild-type mice. In addition, anti-Cad-11 mAb decreased fibrosis at various time points in the bleomycin-induced dermal fibrosis model. In vitro studies demonstrated that Cad-11 regulated the production of transforming growth factor β (TGFβ) by macrophages and the migration of fibroblasts.
CONCLUSION
These data demonstrate that Cad-11 is a mediator of dermal fibrosis and TGFβ production and suggest that Cad-11 may be a therapeutic target in SSc.
目的
系统性硬化症（SSc）是一种慢性自身免疫性疾病，临床上表现为皮肤和内脏器官的进行性纤维化。最近的基因芯片研究表明，钙黏蛋白 11（Cad-11）在 SSc 患者的病变皮肤中表达增加。本研究旨在检验 Cad-11 是皮肤纤维化介质的假说。
方法
使用 SSc 患者和健康对照者的皮肤活检样本进行实时定量聚合酶链反应分析，以评估 Cad-11 的表达，并进行免疫组织化学分析，以确定 Cad-11 的表达模式。为了确定 Cad-11 是否是皮肤纤维化的介质，我们在博来霉素诱导的皮肤纤维化模型中使用 Cad-11 缺陷小鼠和抗 Cad-11 单克隆抗体（mAb）。使用真皮成纤维细胞和骨髓来源的巨噬细胞进行体外研究，以确定 Cad-11 促进组织纤维化的机制。
结果
SSc 患者皮肤活检样本中 Cad-11 的信使 RNA 水平升高，并与改良的罗德纳皮肤厚度评分相关。Cad-11 表达定位于 SSc 皮肤的真皮成纤维细胞和巨噬细胞。与野生型小鼠相比，博来霉素注射的 Cad-11 敲除小鼠皮肤厚度、胶原水平、肌成纤维细胞积累和促纤维化基因表达的病变皮肤中的真皮纤维化明显减弱。此外，抗 Cad-11 mAb 在博来霉素诱导的皮肤纤维化模型的各个时间点均减少纤维化。体外研究表明，Cad-11 调节巨噬细胞转化生长因子 β（TGFβ）的产生和成纤维细胞的迁移。
结论
这些数据表明 Cad-11 是皮肤纤维化和 TGFβ产生的介质，并提示 Cad-11 可能是 SSc 的治疗靶点。
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