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Abstract Number: 2286

Dysregulated Discoidin Domain Receptor 2-Microrna 196a-Mediated Negative Feedback Against Excess Type I Collagen Expression in Scleroderma Dermal Fibroblasts

Katsunari Makino1, Masatoshi Jinnin1, Jun Aoi1, Ikko Kajihara1, Takamitsu Makino2, Keisuke Sakai1, Satoshi Fukushima1, Yuji Inoue1 and Hironobu Ihn2, 1Department of Dermatology and Plastic Surgery, Kumamoto University, Kumamoto, Japan, 2Dermatology and Plastic Surgery, Kumamoto University, Kumamoto, Japan

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Collagen, extracellular matrix proteins, fibroblasts and systemic sclerosis

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Session Information

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud’s – Pathogenesis, Animal Models and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Systemic sclerosis (SSc) is characterized by the excess deposition of collagen in the skin, due to intrinsic transforming growth factor (TGF)-β activation. The discoidin domain receptor 2 (DDR2) is a transmembrane receptor belonging to the receptor tyrosine kinase family. DDR2 is mainly detected in mesenchymal cells and responds to collagen types I, II, III and Χ. This study was undertaken to clarify the expression pattern of DDR2 in SSc and the role in the pathogenesis of SSc.

Methods:

DDR2 expression was evaluated by immunoblotting, immunohistochemistry and real-time PCR. The knockdown or overexpression of DDR2 was performed using siRNA or lentiviral transfection. The microRNA expression was evaluated by real-time PCR. The knockdown or overexpression of microRNA in dermal fibroblasts was performed using microRNA inhibitor or mimic.

Results:

The expression of DDR2 mRNA and protein was significantly decreased in SSc cultured dermal fibroblasts, which was recovered after knockdown TGF-β. The knockdown of DDR2 in normal fibroblasts induced microRNA-196a expression, which led to type I collagen down-regulation, thus indicating that DDR2 itself has a negative effect on microRNA-196a expression and that it induces type I collagen expression. In SSc fibroblasts, however, the DDR2 knockdown did not affect TGF-β signaling and microRNA-196a expression. The microRNA-196a levels were significantly decreased in normal fibroblasts treated with TGF-β and in SSc fibroblasts. Taken together, these findings indicate that, in SSc fibroblasts, the intrinsic TGF-β stimulation induces type I collagen expression and down-regulates DDR2 expression. This probably acts as a negative feedback mechanism against excess collagen expression, since a decreased DDR2 expression is supposed to stimulate the microRNA-196a expression and further change the collagen expression. However, in SSc fibroblasts the microRNA-196a expression was down-regulated by TGF-β signaling.

Conclusion:

DDR2-microRNA 196a-mediated negative feedback against excess type I collagen expression is impaired in SSc fibroblasts. Its impairment may be involved in the pathogenesis of SSc. Investigations of the overall regulatory mechanisms of fibrosis by DDR2 and microRNAs may lead to new therapeutic approaches for this disease.


Disclosure:

K. Makino,
None;

M. Jinnin,
None;

J. Aoi,
None;

I. Kajihara,
None;

T. Makino,
None;

K. Sakai,
None;

S. Fukushima,
None;

Y. Inoue,
None;

H. Ihn,
None.

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