mPGES-1 null mice are resistant to bleomycin-induced skin fibrosis |
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Authors: | Matthew R McCann Roxana Monemdjou Parisa Ghassemi-Kakroodi Hassan Fahmi Gemma Perez Shangxi Liu Xu Shi-wen Sunil K Parapuram Fumiaki Kojima Christopher P Denton David J Abraham Johanne Martel-Pelletier Leslie J Crofford Andrew Leask Mohit Kapoor |
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Institution: | Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CR-CHUM) and Department of Medicine, University of Montreal, 1560 Rue Sherbrooke Est, Montréal, Québec, H2L 4M1, Canada. mohit.kapoor.chum@ssss.gouv.qc.ca. |
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Abstract: | Introduction Microsomal prostaglandin E2 synthase-1 (mPGES-1) is an inducible enzyme that acts downstream of cyclooxygenase (COX) to specifically catalyze the conversion of prostaglandin (PG) H2 to PGE2. mPGES-1 plays a key role in inflammation, pain and arthritis; however, the role of mPGES-1 in fibrogenesis is largely unknown. Herein, we examine the role of mPGES-1 in a mouse model of skin scleroderma using mice deficient in mPGES-1. Methods Wild type (WT) and mPGES-1 null mice were subjected to the bleomycin model of cutaneous skin scleroderma. mPGES-1 expressions in scleroderma fibroblasts and in fibroblasts derived from bleomycin-exposed mice were assessed by Western blot analysis. Degree of fibrosis, dermal thickness, inflammation, collagen content and the number of α-smooth muscle actin (α-SMA)-positive cells were determined by histological analyses. The quantity of the collagen-specific amino acid hydroxyproline was also measured. Results Compared to normal skin fibroblasts, mPGES-1 protein expression was elevated in systemic sclerosis (SSc) fibroblasts and in bleomycin-exposed mice. Compared to WT mice, mPGES-1-null mice were resistant to bleomycin-induced inflammation, cutaneous thickening, collagen production and myofibroblast formation. Conclusions mPGES-1 expression is required for bleomycin-induced skin fibrogenesis. Inhibition of mPGES-1 may be a viable method to alleviate the development of cutaneous sclerosis and is a potential therapeutic target to control the onset of fibrogenesis. |
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