Article

A TGF beta-Responsive Gene Signature Is Associated with a Subset of Diffuse Scleroderma with Increased Disease Severity

Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Journal of Investigative Dermatology (Impact Factor: 6.37). 10/2009; 130(3):694-705. DOI: 10.1038/jid.2009.318
Source: PubMed

ABSTRACT Systemic sclerosis is a complex disease with widespread skin fibrosis and variable visceral organ involvement. Since transforming growth factor-beta (TGFbeta) has been implicated in driving fibrosis in systemic sclerosis, a mechanism-derived gene expression signature was used to assay TGFbeta-responsive gene expression in the skin of patients with systemic sclerosis (SSc). Primary dermal fibroblasts from patients with diffuse SSc (dSSc) and healthy controls were treated with TGFbeta, and the genome-wide gene expression was measured on DNA microarrays over a time course of 24 hours. Eight hundred and ninety-four probes representing 674 uniquely annotated genes were identified as TGFbeta responsive. Expression of the TGFbeta-responsive signature was examined in skin biopsies from 17 dSSc, seven limited SSc (lSSc), three morphea patients, and six healthy controls. The TGFbeta-responsive signature was expressed in 10 out of 17 dSSc skin biopsies, but was not found in lSSc, morphea, or healthy control biopsies. Expression of dSSC the TGFbeta-responsive signature stratifies patients into two major groups, one of which corresponds to the "diffuse-proliferation" intrinsic subset that showed higher modified Rodnan skin score and a higher likelihood of scleroderma lung disease. The TGFbeta-responsive signature is found in only a subset of dSSc patients who could be targeted by specific therapies.

3 Followers
 · 
114 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Tight Skin 2 (Tsk2) mouse model of systemic sclerosis (SSc) has many features of the human disease including tight skin, fibrosis, extracellular matrix abnormalities, and reported antinuclear antibodies (ANA). Here we report that Tsk2/+ mice develop excess dermal fibrosis with age, as skin is not significantly fibrotic until 10 weeks, a full eight weeks after the development of the physical tight skin phenotype. Concomitantly with the tight skin phenotype at two weeks of age, Tsk2/+ mice demonstrate increased levels of total transforming growth factor beta 1 (TGF-β1) and excessive accumulation of dermal elastic fibers. The increase in elastic fibers is not responsible for tight skin, however, because Tsk2/+ mice genetically engineered to lack skin elastic fibers nevertheless have tight skin and fibrosis. Finally, about two months after the first measurable increases of total collagen, a portion of Tsk2/+ mice produce ANAs, but at a similar level to wild-type littermates. The timeline of disease development in the Tsk2/+ mouse shows that fibrosis is progressive, with elastic fiber alterations and TGF-β1 over-production occurring at least two months before bona fide fibrosis, that is not dependent on ANA production.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: There is no universally agreed-upon treatment for the fibrosis of scleroderma. Recently, much information has been generated relating to the fundamental mechanisms underlying this disease. Partly based on these observations, both anti-inflammatory and anti-fibrotic agents have been considered as possible therapies. However, this information has not been successfully translated into clinical practice. In this issue, Pendergrass et al. use genome-wide expression profiling to provide valuable insights into scleroderma. Previously, the authors showed that morphea and "limited" scleroderma patients and a small subset of diffuse scleroderma (dSSc) patients express an "inflammatory" profile, whereas the majority of dSSc patients express a "fibroproliferative" profile. In the current study, the investigators show that the gene expression profile of these patients is fixed over time; i.e., in contrast to a previously held belief, the inflammatory patients do not go on to become fibrotic, and vice versa. These data suggest that expression profiling might be used to design clinical trials for scleroderma. The inflammatory patients might be treated with anti-inflammatory agents, whereas fibroproliferative patients might be treated with antifibrotic agents.
    Journal of Investigative Dermatology 05/2012; 132(5):1329-31. DOI:10.1038/jid.2012.67 · 6.37 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Fibrosis is a deregulated and ultimately defective form of tissue repair that underlies a large number of chronic human diseases, as well as obesity and aging. The pathogenesis of fibrosis involves multiple cell types and extracellular signals, of which transforming growth factor-ß (TGF-ß) is pre-eminent. The prevalence of fibrosis is rising worldwide, and to date no agents has shown clinical efficacy in the attenuating or reversing the process. Recent studies implicate the immediate-early response transcription factor Egr-1 in the pathogenesis of fibrosis. Egr-1 couples acute changes in the cellular environment to sustained alterations in gene expression, and mediates a broad spectrum of biological responses to injury and stress. In contrast to other ligand-activated transcription factors such as NF-κB, c-jun and Smad2/3 that undergo post-translational modification such as phosphorylation and nuclear translocation, Egr-1 activity is regulated via its biosynthesis. Aberrant Egr-1 expression or activity is implicated in cancer, inflammation, atherosclerosis, and ischemic injury and recent studies now indicate an important role for Egr-1 in TGF-ß-dependent profibrotic responses. Fibrosis in various animal models and human diseases such as scleroderma (SSc) and idiopathic pulmonary fibrosis (IPF) is accompanied by aberrant Egr-1 expression. Moreover Egr-1 appears to be required for physiologic and pathological connective tissue remodeling, and Egr-1-null mice are protected from fibrosis. As a novel profibrotic mediator, Egr-1 thus appears to be a promising potential target for the development of anti-fibrotic therapies.
    Matrix biology: journal of the International Society for Matrix Biology 05/2011; 30(4):235-42. DOI:10.1016/j.matbio.2011.03.005 · 3.65 Impact Factor