mPGES-1 null mice are resistant to bleomycin-induced skin fibrosis.
BACKGROUND
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.
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.
Matthew R
MR
McCann
Roxana
R
Monemdjou
Parisa
P
Ghassemi-Kakroodi
Hassan
H
Fahmi
Gemma
G
Perez
Shangxi
S
Liu
Xu
X
Shi-Wen
Sunil K
SK
Parapuram
Fumiaki
F
Kojima
Christopher P
CP
Denton
David J
DJ
Abraham
Johanne
J
Martel-Pelletier
Leslie J
LJ
Crofford
Andrew
A
Leask
Mohit
M
Kapoor
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071876:Prostaglandin-E Synthases; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*
D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse
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