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

Kapoor, M; McCann, M; Liu, SX; Huh, K; Denton, CP; Abraham, DJ; Leask, A; (2009) Loss of Peroxisome Proliferator-Activated Receptor gamma in Mouse Fibroblasts Results in Increased Susceptibility to Bleomycin-Induced Skin Fibrosis. ARTHRITIS RHEUM , 60 (9) 2822 - 2829. 10.1002/art.24761.

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Abstract

Objective. There is increasing evidence that the transcription factor peroxisome proliferator-activated receptor gamma (PPAR gamma) plays an important role in controlling cell differentiation, and that PPAR gamma ligands can modify inflammatory and fibrotic responses. The aim of the present study was to examine the role of PPAR gamma in a mouse model of skin scleroderma, in which mice bearing a fibroblast-specific deletion of PPAR gamma were used.Methods. 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 PPAR gamma were investigated for changes in dermal thick ness, inflammation, collagen content, and the number of a-smooth muscle actin-positive cells. The quantity of the collagen-specific amino acid hydroxyproline was also measured. In addition, the effect of PPAR gamma deletion on transforming growth factor beta 1 (TGF beta 1) signaling in the fibroblasts was investigated.Results. Bleomycin treatment induced marked cutaneous thickening and fibrosis in all treated mice. Deletion of PPAR gamma 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 TGF beta 1 in PPAR-deficient mice.Conclusion. These results indicate that PPAR gamma suppresses fibrogenesis. Specific agonists of PPAR gamma may therefore alleviate the extent of the development of cutaneous sclerosis.

Type: Article
Title: Loss of Peroxisome Proliferator-Activated Receptor gamma in Mouse Fibroblasts Results in Increased Susceptibility to Bleomycin-Induced Skin Fibrosis
DOI: 10.1002/art.24761
Keywords: EMBRYONIC FIBROBLASTS, GENE-EXPRESSION, PPAR-GAMMA, DIFFERENTIATION, SCLERODERMA, CCN2
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: http://discovery.ucl.ac.uk/id/eprint/78370
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