通过种间比较基因组学鉴定系统性硬化症的最佳小鼠模型。
Identification of Optimal Mouse Models of Systemic Sclerosis by Interspecies Comparative Genomics.
机构信息
Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
Brigham and Women's Hospital, Boston, Massachusetts.
出版信息
Arthritis Rheumatol. 2016 Aug;68(8):2003-15. doi: 10.1002/art.39658.
OBJECTIVE
Understanding the pathogenesis of systemic sclerosis (SSc) is confounded by considerable disease heterogeneity. Animal models of SSc that recapitulate distinct subsets of disease at the molecular level have not been delineated. We applied interspecies comparative analysis of genomic data from multiple mouse models of SSc and patients with SSc to determine which animal models best reflect the SSc intrinsic molecular subsets.
METHODS
Gene expression measured in skin from mice with sclerodermatous graft-versus-host disease (GVHD), bleomycin-induced fibrosis, Tsk1/+ or Tsk2/+ mice was mapped to human orthologs and compared to SSc skin biopsy-derived gene expression. Transforming growth factor β (TGFβ) activation was assessed using a responsive signature in mice, and tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) expression was measured in SSc patient and mouse skin.
RESULTS
Gene expression in skin from mice with sclerodermatous GVHD and bleomycin-induced fibrosis corresponded to that in SSc patients in the inflammatory molecular subset. In contrast, Tsk2/+ mice showed gene expression corresponding to the fibroproliferative SSc subset. Enrichment of a TGFβ-responsive signature was observed in both Tsk2/+ mice and mice with bleomycin-induced skin fibrosis. Expression of TNFRSF12A (the TWEAK receptor/fibroblast growth factor-inducible 14) was elevated in skin from patients with fibroproliferative SSc and the skin of Tsk2/+ mice.
CONCLUSION
This study reveals similarities in cutaneous gene expression between distinct mouse models of SSc and specific molecular subsets of the disease. Different pathways underlie the intrinsic subsets including TGFβ, interleukin-13 (IL-13), and IL-4. We identify a novel target, Tnfrsf12a, with elevated expression in skin from patients with fibroproliferative SSc and Tsk2/+ mice. These findings will inform mechanistic and translational preclinical studies in SSc.
目的
系统性硬化症（SSc）的发病机制较为复杂，存在较大的疾病异质性。目前尚未明确能够在分子水平再现疾病不同亚型的 SSc 动物模型。本研究通过对多种 SSc 小鼠模型和 SSc 患者的基因组数据进行种间比较分析，以确定哪些动物模型最能反映 SSc 的内在分子亚型。
方法
将硬皮病移植物抗宿主病（GVHD）、博来霉素诱导纤维化、Tsk1/+或 Tsk2/+小鼠皮肤中的基因表达进行物种映射，并与 SSc 皮肤活检基因表达进行比较。在小鼠中使用响应性特征评估转化生长因子β（TGFβ）的激活情况，并测量 SSc 患者和小鼠皮肤中肿瘤坏死因子受体超家族成员 12A（TNFRSF12A）的表达。
结果
硬皮病 GVHD 和博来霉素诱导纤维化小鼠皮肤中的基因表达与 SSc 患者的炎症分子亚型相对应。相比之下，Tsk2/+小鼠表现出与 SSc 纤维增生性亚型相对应的基因表达。在 Tsk2/+小鼠和博来霉素诱导的皮肤纤维化小鼠中均观察到 TGFβ 响应性特征的富集。在纤维增生性 SSc 患者皮肤和 Tsk2/+小鼠皮肤中，TNFRSF12A（TWEAK 受体/成纤维细胞生长因子诱导 14）的表达升高。
结论
本研究揭示了不同 SSc 小鼠模型与疾病特定分子亚型之间皮肤基因表达的相似性。不同的通路（包括 TGFβ、白细胞介素 13（IL-13）和 IL-4）是内在亚型的基础。我们确定了一个新的靶标 Tnfrsf12a，其在纤维增生性 SSc 患者皮肤和 Tsk2/+小鼠皮肤中的表达升高。这些发现将为 SSc 的机制和转化前临床研究提供信息。
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