Role of Rac1 in a bleomycin-induced scleroderma model using fibroblast-specific Rac1-knockout mice.
OBJECTIVE
Activated adhesive signaling is a hallmark of fibroblasts isolated from the scars of scleroderma (systemic sclerosis [SSc]) lesions. Rac1 plays a key role in adhesive signaling. The aim of the present study was to examine the role of Rac1 in bleomycin-induced scleroderma, using mice with a fibroblast-specific deletion of Rac1.


METHODS
Cutaneous sclerosis was induced by subcutaneous injection of bleomycin. Control groups were treated with phosphate buffered saline. Mice with a fibroblast-specific deletion of Rac1 and control mice were investigated. Dermal thickness, inflammation, collagen production, and the number of alpha-smooth muscle actin-positive cells were determined. The quantity of the collagen-specific amino acid hydroxyproline was also measured.


RESULTS
Bleomycin treatment induced marked cutaneous thickening, inflammation, and fibrosis in control mice. Conversely, deletion of Rac1 resulted in resistance to bleomycin-induced fibrosis and inflammation.


CONCLUSIONS
Rac1 expression by fibroblasts is required for fibrogenesis. Inhibition of Rac1 may be a viable method to alleviate the development of cutaneous sclerosis.
Liu
Shangxi
S
University of Western Ontario, London, Ontario, Canada.
Kapoor
Mohit
M
Shi-wen
Xu
X
Kennedy
Laura
L
Denton
Christopher P
CP
Glogauer
Michael
M
Abraham
David J
DJ
Leask
Andrew
A
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects; D001761:Bleomycin / Q000009:adverse effects; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics*; D012594:Scleroderma, Localized / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D020744:rac GTP-Binding Proteins / Q000235:genetics*; D020830:rac1 GTP-Binding Protein
D000903:Antibiotics, Antineoplastic; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D001761:Bleomycin; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein