Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Cadherin-11 in Systemic Sclerosis and Its Role in Dermal Fibrosis.

Wu3,  Minghua, Brenner1,  Michael B., Mayes4,  Maureen D., Arnett5,  Frank C., Tan6,  Filemon K., Agarwal2,  Sandeep K.

Brigham & Womens Hospital, Boston, MA
Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, TX
Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston (UTHSC-H), Houston, TX
University of Texas-Houston, Houston, TX
UT Medical School, Houston, TX
UT-Houston Med School, Houston, TX

Background:

Cadherin-11 (Cad-11) is a mesenchymal cadherin initially identified in osteoblasts but subsequently found to be expressed on other cells including synovial fibroblasts where it confers a mesenchymal phenotype and promotes cellular invasion. Cad-11 has been reported to be increased during wound healing. Recently, Cad-11 was observed to be upregulated in scleroderma (SSc) skin in two independent microarray studies. These results led to the hypothesis that Cad-11 is a critical mediator of dermal fibrosis.

Methods:

SSc and normal skin biopsies were used for qRTPCR to quantitate Cad-11 levels and for immunohistological (IHC) analyses to determine the expression pattern of Cad-11. Dermal fibroblasts were stimulated with TGFb and qRTPCR was used to determine if TGFb increased Cad-11 expression. To determine if Cad-11 is a mediator of dermal fibrosis, Cad-11 deficient (def) and wild type (WT) mice were compared using the bleomycin (bleo) induced skin fibrosis model. Anti-Cad-11 monoclonal antibodies (mAb) also were used to confirm these findings in the bleo-induced skin fibrosis model.

Results:

Cad-11 transcript levels were increased in SSc skin biopsies (n=6) relative to healthy control skin biopsies (n=9). IHC analyses of skin biopsies demonstrated Cad-11 reactivity in the dermis of SSc biopsies, but not control biopsies, predominantly on fibroblast-like cells. TGFb upregulated Cad11 expression on cultured dermal fibroblasts from healthy controls and SSc patients. Using the bleo-induced dermal fibrosis model, Cad-11 def. mice had markedly attenuated dermal fibrosis as quantitated by skin thickness (Cad11 def:194±14 mm, WT: 255±17 mm, p=0.003), collagen levels (Cad11 def: 230±24 mg/mg, WT: 319±20 mg/mg, p=0.01) and myofibroblast accumulation in the lesional skin. Administration of two neutralizing anti-Cad-11mAb to WT mice resulted in a significant amelioration of collagen deposition and dermal thickness in bleo-induced dermal fibrosis. Lastly, Col1a1 and CTGF mRNA levels but not IL-6 levels were significantly decreased in lesional skin of Cad-11 def. compared to WT mice.

Conclusions:

These results demonstrate that Cad-11 is a critical mediator of dermal fibrosis, and suggest that Cad-11 is a potential therapeutic target in SSc.

To cite this abstract, please use the following information:
Wu, Minghua, Brenner, Michael B., Mayes, Maureen D., Arnett, Frank C., Tan, Filemon K., Agarwal, Sandeep K.; Cadherin-11 in Systemic Sclerosis and Its Role in Dermal Fibrosis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :603
DOI: 10.1002/art.28371

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