Loss of Peroxisome Proliferator–Activated Receptor ␥ in Mouse Fibroblasts Results in Increased Susceptibility to Bleomycin-Induced Skin Fibrosis

University of Western Ontario, London, Ontario, Canada.
Arthritis & Rheumatology (Impact Factor: 7.76). 09/2009; 60(9):2822-9. DOI: 10.1002/art.24761
Source: PubMed


There is increasing evidence that the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) plays an important role in controlling cell differentiation, and that PPARgamma ligands can modify inflammatory and fibrotic responses. The aim of the present study was to examine the role of PPARgamma in a mouse model of skin scleroderma, in which mice bearing a fibroblast-specific deletion of PPARgamma were used.
Cutaneous sclerosis was induced by subcutaneous injection of bleomycin, while untreated control groups were injected with phosphate buffered saline. Mice bearing a fibroblast-specific deletion of PPARgamma were investigated for changes in dermal thickness, inflammation, collagen content, and the number of alpha-smooth muscle actin-positive cells. The quantity of the collagen-specific amino acid hydroxyproline was also measured. In addition, the effect of PPARgamma deletion on transforming growth factor beta1 (TGFbeta1) signaling in the fibroblasts was investigated.
Bleomycin treatment induced marked cutaneous thickening and fibrosis in all treated mice. Deletion of PPARgamma resulted in enhanced susceptibility to bleomycin-induced skin fibrosis, as indicated by increases in all measures of skin fibrosis and enhanced sensitivity of fibroblasts to TGFbeta1 in PPAR-deficient mice.
These results indicate that PPARgamma suppresses fibrogenesis. Specific agonists of PPARgamma may therefore alleviate the extent of the development of cutaneous sclerosis.

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Available from: Matthew R Mccann, Apr 09, 2015
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    • "PPAR-g activation strongly correlates with the TGF-b/Smad pathway as it directly antagonizes Smad3 or downregulates CTGF expression [55] [56]. Overexpression of PPAR-g prevents tissue fibrosis, whereas its loss increases fibrosis [34] [57]. PPAR-g agonists attenuate fibrosis in several organs including the intestine and these antifibrotic effects are abolished by PPAR-g selective antagonists [58] [59]. "
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    ABSTRACT: Abstract Intestinal fibrosis is a common complication of the inflammatory bowel diseases (IBDs). It becomes clinically apparent in >30% of patients with Crohn's disease (CD) and in about 5% with ulcerative colitis (UC). Fibrosis is a consequence of local chronic inflammation and is characterized by excessive extracellular matrix (ECM) protein deposition. ECM is produced by activated myofibroblasts, which are modulated by both, profibrotic and antifibrotic factors. Fibrosis depends on the balance between the production and degradation of ECM proteins. This equilibrium can be impacted by a complex and dynamic interaction between profibrotic and antifibrotic mediators. Despite the major therapeutic advances in the treatment of active inflammation in IBD over the past two decades, the incidence of intestinal strictures in CD has not significantly changed as the current anti-inflammatory therapies neither prevent nor reverse the established fibrosis and strictures. This implies that control of intestinal inflammation does not necessarily affect the associated fibrotic process. The conventional view that intestinal fibrosis is an inevitable and irreversible process in patients with IBD is also gradually changing in light of an improved understanding of the cellular and molecular mechanisms that underline the pathogenesis of fibrosis. Comprehension of the mechanisms of intestinal fibrosis is thus vital and may pave the way for the developments of antifibrotic agents and new therapeutic approaches in IBD.
    Scandinavian Journal of Gastroenterology 01/2015; 50(1):53-65. DOI:10.3109/00365521.2014.968863 · 2.36 Impact Factor
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    • "PPAR-γ ligands repress TGFβ-induced myofibroblast differentiation and activation by targeting the PI3K/Akt and Smad3 pathways, respectively.55,56 Overexpression of PPARγ prevents the development of tissue fibrosis, whereas its loss increases susceptibility to fibrosis.57,58 All these findings could explain the ability of PPARγ to interfere in multiple phases of the tissue fibrotic processes. "
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    ABSTRACT: A simultaneous action of several pro-fibrotic mediators appears relevant in the development of fibrosis. There are evidences that transforming growth factor-β (TGF-β)/Smad3 pathway forms with αvβ6 integrin, mammalian target of Rapamycin (mTOR) and peroxisome proliferator-activated receptor-γ (PPARγ) a complex signalling network with extensive crosstalk and strong effects on fibrosis development. The present study evaluated the expression of TGFβ, Smad3, αvβ6 integrin, mTOR and PPARγ in 2, 4, 6-trinitrobenzenesulphonic acid (TNBS)-induced colorectal fibrosis in Smad3 wild-type (WT) and null mice. Smad3 WT mice treated with TNBS developed a marked colorectal fibrosis and showed a concomitant up-regulation of TGFβ, Smad3, αvβ6 and mTOR and a reduction of PPARγ expression. On the other hand, Smad3 Null mice similarly treated with TNBS did not develop fibrosis and showed a very low or even absent expression of TGFβ, Smad3, αvβ6 and mTOR and a marked over-expression of PPARγ. At the same time the expression of α-smooth muscle actin (a marker of activated myofibroblasts), collagen I-III and connective tissue growth factor (a downstream effector of TGFβ/Smad3-induced extracellular matrix proteins) were up-regulated in Smad3 WT mice treated with TNBS compared to Null TNBS-treated mice. These preliminary results suggest a possible interaction between these pro-fibrotic molecules in the development of intestinal fibrosis.
    European journal of histochemistry: EJH 10/2013; 57(4):e40. DOI:10.4081/ejh.2013.e40 · 2.04 Impact Factor
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    • "We have previously demonstrated reduced cutaneous PPAR-γ expression in mice with bleomycin-induced scleroderma [75]. Mice with fibroblast-specific PPAR-γ deletion showed increased susceptibility to bleomycin-induced scleroderma [82]. In vitro, PPAR-γ-deficient fibroblasts showed constitutive TGF-β secretion and enhanced stimulation of type I collagen and α-SMA production [82, 83]. "
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    ABSTRACT: The intractable process of fibrosis underlies the pathogenesis of systemic sclerosis (SSc) and other diseases, and in aggregate contributes to 45% of deaths worldwide. Because currently there is no effective anti-fibrotic therapy, a better understanding of the pathways and cellular differentiation programs underlying fibrosis are needed. Emerging evidence points to a fundamental role of the nuclear hormone receptor peroxisome proliferator activated receptor-γ (PPAR-γ) in modulating fibrogenesis. While PPAR-γ has long been known to be important in lipid metabolism and in glucose homeostasis, its role in regulating mesenchymal cell biology and its association with pathological fibrosis had not been appreciated until recently. This article highlights recent studies revealing a consistent association of fibrosis with aberrant PPAR-γ expression and activity in various forms of human fibrosis and in rodent models, and reviews studies linking genetic manipulation of the PPAR-γ pathway in rodents and fibrosis. We survey the broad range of anti-fibrotic activities associated with PPAR-γ and the underlying mechanisms. We also summarize the emerging data linking PPAR-γ dysfunction and pulmonary arterial hypertension (PAH), which together with fibrosis is responsible for the mortality in patients in SSc. Finally, we consider current and potential future strategies for targeting PPAR-γ activity or expression as a therapy for controlling fibrosis.
    The Open Rheumatology Journal 06/2012; 6(1):103-15. DOI:10.2174/1874312901206010103
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