title: Discoidin domain receptor 2-microRNA 196a-mediated negative feedback against excess type I collagen expression is impaired in scleroderma dermal fibroblasts.
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.
authors: Department of Dermatology and Plastic Surgery, Kumamoto University, Kumamoto, Japan.
authors: Katsunari
authors: K
authors: Makino
authors: Masatoshi
authors: M
authors: Jinnin
authors: Jun
authors: J
authors: Aoi
authors: Ayaka
authors: A
authors: Hirano
authors: Ikko
authors: I
authors: Kajihara
authors: Takamitsu
authors: T
authors: Makino
authors: Keisuke
authors: K
authors: Sakai
authors: Satoshi
authors: S
authors: Fukushima
authors: Yuji
authors: Y
authors: Inoue
authors: Hironobu
authors: H
authors: Ihn
mesh_terms: D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis*; D020405:Dermis / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000070818:Discoidin Domain Receptors; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D024042:Collagen Type I; C542543:MIRN196 microRNA, human; D035683:MicroRNAs; D011975:Receptors, Mitogen; D016212:Transforming Growth Factor beta; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases