Project description:Pathway expression analysis in systemic sclerosis revealed key mediators driving pathology within each of the intrinsic gene expression subsets. Genome-wide expression profiling in systemic sclerosis (SSc) has identified four 'intrinsic' subsets of disease (fibroproliferative, inflammatory, limited, and normal-like), each of which appear to be driven by distinct signaling pathways. Here we examine experimentally derived gene expression signatures for thirteen agonists to better understand the molecular mechanisms underlying each intrinsic subsets. Pathway-specific gene signatures were compared against skin biopsy microarray data consisting of 329 microarray hybridizations from 287 unique biopsies representing 111 patients. Hierarchical clustering recapitulated the four SSc 'intrinsic' gene expression subsets, along with an intermediate subset exhibiting both inflammatory and fibroproliferative gene expression signatures. The fibroproliferative subset is most strongly associated with the PDGF gene signature, while the inflammatory subset demonstrated strong activation of NF-kappaB, characterized by early induction of TH2 signals, which transitions to a more TH17-like immune response over time. The limited subset was associated with IFNalpha signaling, combined with strong downregulation of PDGF signaling. The inflammatory-proliferative subset shows downregulation of NF-kappaB-associated pathways in conjunction with increased PDGF signaling, suggestive of a transitional state linking the inflammatory and fibroproliferative subsets. IL-13 signaling was strongly associated with early disease, while TGFbeta signaling was associated with more severe disease. Together these data suggest a multi-step, progressive model of disease pathogenesis driven by distinct pathways. Targeting these pathways based upon a patient's underlying disease subset should improve therapeutic outcomes. In vitro treatment of human dermal fibroblasts was performed to identify pathway-specific gene signatures. These gene signatures were then compared against systemic sclerosis skin biopsy microarrays to determine the overall contribution of each pathway to disease. This study includes re-analysis of 247 skin biopsy samples from GSE9285, GSE32413, and GSE45485. Links to these Samples are provided below. The re-processed normalized data for these Samples are included in the supplementary file 'GSE56308_247_Skin_Biopsy_Reanalysis_Samples.txt'.

Project description:Systemic sclerosis is a connective tissue disease affecting skin and internal organs, characterized by a triad of inflammation, vasculopathy and progressive fibrosis, due to deposition of mainly type I collagen. Out of the intricate mechanisms involved in the pathogenesis of the disease, evidence indicates that TGFbeta signaling plays a central role in mediating the effects of several pro-fibrotic effectors. In addition, TGFbeta is induced by hypoxia in cultured fibroblasts, an observation suggesting a role for this cytokine in linking vasculopathy and fibrosis in the disease. Not surprisingly, TGFbeta and Wnt signaling are among the most prevalent pathways found in global gene expression studies performed on systemic sclerosis skin biopsies. In this perspective, modulation of TGFbeta activity remains a top therapeutic target in systemic sclerosis drug development. We recently performed whole-body magnetic resonance imaging (MRI) studies in systemic sclerosis patients, and evidenced deep connective tissue infiltrates surrounding tendons in patients with active disease, and tendon friction rubs. Tenosynovitis and arthritis were also found by MRI in one third of the patients. We performed tenosynovial biopsies in patients with clinically active tenosynovitis, in order to evaluate whether such samples would provide additional information on disease mechanisms. Here, we report that these samples are characterized by the over-expression of genes involved in fibrosis, TGFbeta/Wnt signaling, chemokines and cytokines, but also by the concurrent over-expression of several ubiquitin-specific peptidases (USPs). Among the USPs overexpressed in systemic sclerosis tenosynovial biopsies, USP15 is known to specifically deubiquitinate SMAD3, and the TGFbeta Receptor 1. These results triggered us to perform additional experiments in order to test whether USP15 overexpression plays a role in the pathogenesis of systemic sclerosis via decreased ubiquitin-mediated degradation of proteins involved in TGFbeta signaling.

Dataset Information

Multi-tissue functional genomic study of systemic sclerosis

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