A TGFβ-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: 7.22). 10/2009; 130(3):694-705. DOI: 10.1038/jid.2009.318
Source: PubMed


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.

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    • "Perhaps epidermal dendritic cells are critical producers of TGF-β1 in Tsk2/+ skin (Gruschwitz and Hornstein, 1992). The proposed causal relationship of TGF-β1 to skin fibrosis and the physical phenotype of tight skin in Tsk2/+ mice needs verification, but we note that at two weeks, skin from male Tsk2/+ mice expresses 170%–300% more mRNA for five TGF-β1 signature proteins (collagen type V, alpha 2; elastin; fibulin-2; α-smooth muscle actin; and cartilage oligomeric protein) (Piscaglia et al., 2009; Kurpinski et al., 2010; Sargent et al., 2010) as assessed by quantitative real-time PCR (data not shown). "
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    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.
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    • "Consistent with the presence of myofibroblasts in SSc and wounding, gene expression profiling studies demonstrate a number of genes differentially regulated in wound healing fibroblasts and those derived from fibrotic regions of SSc patients [14]. Comprehensive transcriptional analysis of skin biopsies has demonstrated systematic differences in the gene expression profile of dermal fibroblasts from SSc patients into subsets including inflammatory and transforming growth factor (TGF)-β gene signatures [15,16]. The different gene expression profiles exhibited by fibroblasts from SSc patients may reflect the diverse origins of the cells that contribute to the formation of myofibroblasts. "
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    ABSTRACT: Scleroderma (systemic sclerosis; SSc) is characterised by fibrosis of the skin and internal organs in the context of autoimmunity and vascular perturbation. Overproduction of extracellular matrix components and loss of specialised epithelial structures are analogous to the process of scar formation after tissue injury. Fibroblasts are the resident cells of connective tissue that become activated at sites of damage and are likely to be important effector cells in SSc. Differentiation into myofibroblasts is a hallmark process, although the mechanisms and cellular origins of this important fibroblastic cell are still unclear. This article reviews fibroblast biology in the context of SSc and highlights the potentially important place of fibroblast effector cells in fibrosis. Moreover, the heterogeneity of fibroblast properties, multiplicity of regulatory pathways and diversity of origin for myofibroblasts may underpin clinical diversity in SSc, and provide novel avenues for targeted therapy.
    Full-text · Article · Jun 2013 · Arthritis research & therapy
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    • "Moreover, explanted scleroderma fibroblasts showed reduced PPAR-γ [24]. We have previously identified a scleroderma subset with impaired PPAR-γ signaling that was associated with a strong 'TGF-ß-activated gene signature' in skin biopsies [42]. These scleroderma patients had a rather aggressive form of disease with extensive skin fibrosis. "
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    ABSTRACT: Fibrosis in scleroderma is associated with collagen deposition and myofibroblast accumulation. Peroxisome proliferator activated receptor gamma (PPAR-γ), a master regulator of adipogenesis, inhibits profibrotic responses induced by transforming growth factor-ß (TGF-β), and its expression is impaired in scleroderma. The roles of adiponectin, a PPAR-γ regulated pleiotropic adipokine, in regulating the response of fibroblasts and in mediating the effects of PPAR-γ are unknown. Regulation of fibrotic gene expression and TGF-ß signaling by adiponectin and adenosine monophosphate protein-activated (AMP) kinase agonists were examined in normal fibroblasts in monolayer cultures and in three-dimensional skin equivalents. AdipoR1/2 expression on skin fibroblasts was determined by real-time quantitative PCR. Adiponectin, an adipokine directly regulated by PPAR-γ, acts as a potent anti-fibrotic signal in normal and scleroderma fibroblasts that abrogates the stimulatory effects of diverse fibrotic stimuli and reduces elevated collagen gene expression in scleroderma fibroblasts. Adiponectin responses are mediated via AMP kinase, a fuel-sensing cellular enzyme that is necessary and sufficient for down-regulation of fibrotic genes by blocking canonical Smad signaling. Moreover, we demonstrate that endogenous adiponectin accounts, at least in part, for the anti-fibrotic effects exerted by ligands of PPAR-γ. These findings reveal a novel link between cellular energy metabolism and extracellular matrix homeostasis converging on AMP kinase. Since the levels of adiponectin as well as its receptor are impaired in scleroderma patients with progressive fibrosis, the present results suggest a potential role for defective adiponectin expression or function in progressive fibrogenesis in scleroderma and other chronic fibrosing conditions. Restoring the adiponectin signaling axis in fibroblasts might, therefore, represent a novel pharmacological approach to controlling fibrosis.
    Full-text · Article · Oct 2012 · Arthritis research & therapy
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