RRC ID 34819
Author Makino K, Jinnin M, Aoi J, Hirano A, Kajihara I, Makino T, Sakai K, Fukushima S, Inoue Y, Ihn H.
Title Discoidin domain receptor 2-microRNA 196a-mediated negative feedback against excess type I collagen expression is impaired in scleroderma dermal fibroblasts.
Journal J. Invest. Dermatol.
Abstract Systemic sclerosis (SSc) is characterized by excess collagen deposition in the skin, due to intrinsic transforming growth factor-β (TGF-β) activation. We tried to determine the expression and the role of discoidin domain receptor 2 (DDR2) in SSc. The expression of DDR2 mRNA and protein was significantly decreased in SSc dermal fibroblasts, which was recovered by knocking down TGF-β. The knockdown of DDR2 in normal fibroblasts induced microRNA-196a expression, which led to type I collagen downregulation, indicating that DDR2 itself has a negative effect on microRNA-196a expression and inducible effect on 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 our data indicate that, in SSc fibroblasts, intrinsic TGF-β stimulation induces type I collagen expression, and also downregulates DDR2 expression. This probably acts as a negative feedback mechanism against excess collagen expression, as 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 downregulated by TGF-β signaling. DDR2-microRNA-196a pathway may be a previously unreported negative feedback system, and its impairment may be involved in the pathogenesis of SSc.
Volume 133(1)
Pages 110-9
Published 2013-1
DOI 10.1038/jid.2012.252
PII S0022-202X(15)35961-3
PMID 22832484
MeSH Cells, Cultured Collagen Type I / biosynthesis* Dermis / drug effects Dermis / metabolism* Dermis / pathology Discoidin Domain Receptors Feedback, Physiological / drug effects Feedback, Physiological / physiology* Fibroblasts / drug effects Fibroblasts / metabolism* Fibroblasts / pathology Gene Expression Regulation / drug effects Gene Expression Regulation / physiology Gene Knockdown Techniques Humans MicroRNAs / genetics MicroRNAs / metabolism* Receptor Protein-Tyrosine Kinases / genetics Receptor Protein-Tyrosine Kinases / metabolism* Receptors, Mitogen / genetics Receptors, Mitogen / metabolism* Scleroderma, Systemic / drug therapy Scleroderma, Systemic / metabolism* Signal Transduction / drug effects Signal Transduction / physiology Transforming Growth Factor beta / genetics Transforming Growth Factor beta / metabolism Transforming Growth Factor beta / pharmacology
IF 6.448
Times Cited 12
DNA material pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393) CSII-EF-RfA (RDB04387).