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Identification of Optimal Mouse Models of Systemic Sclerosis by Interspecies Comparative Genomics
Author(s) -
Sargent Jennifer L.,
Li Zhenghui,
Aliprantis Antonios O.,
Greenblatt Matthew,
Lemaire Raphael,
Wu Minghua,
Wei Jun,
Taroni Jaclyn,
Harris Adam,
Long Kristen B.,
Burgwin Chelsea,
Artlett Carol M.,
Blankenhorn Elizabeth P.,
Lafyatis Robert,
Varga John,
Clark Stephen H.,
Whitfield Michael L.
Publication year - 2016
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39658
Subject(s) - biology , fibrosis , transforming growth factor , pathogenesis , gene expression , pathology , tumor necrosis factor alpha , gene signature , gene , immunology , cancer research , medicine , genetics , microbiology and biotechnology
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.