title: Increased accumulation of extracellular thrombospondin-2 due to low degradation activity stimulates type I collagen expression in scleroderma fibroblasts.
abstract: The aim of the present study was to determine the expression and role of thrombospondin-2 (TSP-2) in systemic sclerosis (SSc). Both TSP-2 mRNA levels and protein synthesis in cell lysates were significantly lower in cultured SSc fibroblasts than in normal fibroblasts; however, the TSP-2 protein that accumulated in the conditioned medium of SSc fibroblasts was up-regulated, compared with that of normal fibroblasts, because of an increase in the half-life of the protein. In vivo serum TSP-2 levels were higher in SSc patients than in healthy control subjects, and SSc patients with elevated serum TSP-2 levels tended to have pitting scars and/or ulcers. TSP-2 knockdown resulted in the down-regulation of type I collagen expression and the up-regulation of miR-7, one of the miRNAs with an inhibitory effect on collagen expression. Expression levels of miR-7 were also up-regulated in SSc dermal fibroblasts both in vivo and in vitro. Taken together, these findings suggest that the increased extracellular TSP-2 deposition in SSc fibroblasts may contribute to tissue fibrosis by inducing collagen expression. Down-regulation of intracellular TSP-2 synthesis and the subsequent miR-7 up-regulation in SSc fibroblasts may be due to a negative feedback mechanism that prevents increased extracellular TSP-2 deposition and/or tissue fibrosis. Thus, TSP-2 may play an important role in the maintenance of fibrosis and angiopathy in patients with SSc.
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Ikko
authors.initials: I
authors.lastname: Kajihara
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Jinnin
authors.forename: Keitaro
authors.initials: K
authors.lastname: Yamane
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Makino
authors.forename: Noritoshi
authors.initials: N
authors.lastname: Honda
authors.forename: Toshikatsu
authors.initials: T
authors.lastname: Igata
authors.forename: Shinichi
authors.initials: S
authors.lastname: Masuguchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukushima
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Minoru
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Manabu
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ihn
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D012595:Scleroderma, Systemic / Q000378:metabolism*; D012867:Skin / Q000378:metabolism; D019699:Thrombospondins / Q000096:biosynthesis / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation; D055815:Young Adult; D000099262:Thrombospondin 2
chemical_list: D024042:Collagen Type I; D020781:Matrix Metalloproteinase 1; D020778:Matrix Metalloproteinase 2; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019699:Thrombospondins; D016212:Transforming Growth Factor beta; D000099262:Thrombospondin 2; C549242:MIRN7-1 microRNA, human