Identification of cadherin 11 as a mediator of dermal fibrosis and possible role in systemic sclerosis.
OBJECTIVE
Systemic sclerosis (SSc) is a chronic autoimmune disease clinically manifesting as progressive fibrosis of the skin and internal organs. Recent microarray studies demonstrated that cadherin 11 (Cad-11) expression is increased in the affected skin of patients with SSc. The purpose of this study was to examine our hypothesis that Cad-11 is a mediator of dermal fibrosis.


METHODS
Biopsy samples of skin from SSc patients and healthy control subjects were used for real-time quantitative polymerase chain reaction analysis to assess Cad-11 expression and for immunohistochemistry to determine the expression pattern of Cad-11. To determine whether Cad-11 is a mediator of dermal fibrosis, Cad-11-deficient mice and anti-Cad-11 monoclonal antibodies (mAb) were used in the bleomycin-induced dermal fibrosis model. In vitro studies with dermal fibroblasts and bone marrow-derived macrophages were used to determine the mechanisms by which Cad-11 contributes to the development of tissue fibrosis.


RESULTS
Levels of messenger RNA for Cad-11 were increased in skin biopsy samples from patients with SSc and correlated with the modified Rodnan skin thickness scores. Cad-11 expression was localized to dermal fibroblasts and macrophages in SSc skin. Cad-11-knockout mice injected with bleomycin had markedly attenuated dermal fibrosis, as quantified by measurements of skin thickness, collagen levels, myofibroblast accumulation, and profibrotic gene expression, in lesional skin as compared to the skin of wild-type mice. In addition, anti-Cad-11 mAb decreased fibrosis at various time points in the bleomycin-induced dermal fibrosis model. In vitro studies demonstrated that Cad-11 regulated the production of transforming growth factor β (TGFβ) by macrophages and the migration of fibroblasts.


CONCLUSIONS
These data demonstrate that Cad-11 is a mediator of dermal fibrosis and TGFβ production and suggest that Cad-11 may be a therapeutic target in SSc.
University of Texas Health Science Center at, Houston.
Minghua
M
Wu
Mesias
M
Pedroza
Robert
R
Lafyatis
Anuh-Teresa
AT
George
Maureen D
MD
Mayes
Shervin
S
Assassi
Filemon K
FK
Tan
Michael B
MB
Brenner
Sandeep K
SK
Agarwal
D000328:Adult; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012595:Scleroderma, Systemic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D015820:Cadherins; D016212:Transforming Growth Factor beta; C086960:osteoblast cadherin