Disruption of tumor necrosis factor receptor p55 impairs collagen turnover in experimentally induced sclerodermic skin fibroblasts.
OBJECTIVE
To determine the role of tumor necrosis factor receptor p55 (TNFRp55)-mediated signaling in the pathogenesis of scleroderma.


METHODS
A murine model of scleroderma that closely resembles systemic sclerosis in humans was used. Wild-type and TNFRp55-deficient (TNFRp55(-/-)) mice received a subcutaneous injection of bleomycin each day. The extent of skin fibrosis was determined by measurements of the dermal thickness, as well as histologic examinations. Expression levels of fibrogenic cytokines, procollagen alpha1, and matrix metalloproteinase 1 (MMP-1), MMP-2, and MMP-9 messenger RNA (mRNA) were analyzed, both in vivo and in vitro, by reverse transcriptase-polymerase chain reaction assay or Western blotting.


RESULTS
TNFRp55(-/-) mice began to develop severe sclerotic changes of the dermis on day 3 of the subcutaneous injections of bleomycin, while wild-type mice did not. The expression levels of fibrogenic cytokines, procollagen alpha1, and MMP-2 and MMP-9 mRNA were unaffected in the skin of both wild-type and TNFRp55(-/-) mice, with or without bleomycin treatment. Induction of MMP-1 expression was significantly inhibited in the skin from bleomycin-treated TNFRp55(-/-) mice, and this phenomenon was also observed in vitro.


CONCLUSIONS
These results indicated that signaling mediated by TNFRp55 plays an essential role in MMP-1 expression and a key role in the collagen degradation process in this murine model. This study might provide a basis for understanding the pathogenesis of scleroderma and formulating therapeutic intervention.
Murota
Hiroyuki
H
Nagasaki University Graduate School of Biomedical Sciences, Japan.
Hamasaki
Youichiro
Y
Nakashima
Tomoki
T
Yamamoto
Kazuo
K
Katayama
Ichiro
I
Matsuyama
Toshifumi
T
D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D015153:Blotting, Western; D003094:Collagen / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
D016207:Cytokines; D017931:DNA Primers; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D001761:Bleomycin; D003094:Collagen