Journal article
Identification of Optimal Mouse Models of Systemic Sclerosis by Interspecies Comparative Genomics
Arthritis & rheumatology (Hoboken, N.J.), v 68(8), pp 2003-2015
Aug 2016
PMID: 26945694
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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.
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.
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.
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Details
- Title
- Identification of Optimal Mouse Models of Systemic Sclerosis by Interspecies Comparative Genomics
- Creators
- Jennifer L Sargent - Dartmouth CollegeZhenghui Li - Dartmouth CollegeAntonios O Aliprantis - Brigham and Women's HospitalMatthew Greenblatt - Brigham and Women's HospitalRaphael Lemaire - Boston UniversityMing-Hua Wu - Feinberg School of Medicine, Northwestern University, Chicago, IllinoisJun Wei - Northwestern UniversityJaclyn Taroni - Dartmouth CollegeAdam Harris - University of Connecticut Health CenterKristen B Long - Drexel UniversityChelsea Burgwin - Drexel UniversityCarol M Artlett - Drexel UniversityElizabeth P Blankenhorn - Drexel UniversityRobert Lafyatis - Boston UniversityJohn Varga - Northwestern UniversityStephen H Clark - University of Connecticut Health CenterMichael L Whitfield - Dartmouth College
- Publication Details
- Arthritis & rheumatology (Hoboken, N.J.), v 68(8), pp 2003-2015
- Publisher
- Wiley
- Grant note
- P30 CA023108 / NCI NIH HHS R01 AR051089 / NIAMS NIH HHS R01 AR061384 / NIAMS NIH HHS P30 AR061271 / NIAMS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000383498400025
- Scopus ID
- 2-s2.0-84979555036
- Other Identifier
- 991019168695504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Rheumatology