title: Cooperative interaction of CTGF and TGF-β in animal models of fibrotic disease.
abstract: BACKGROUND
  Connective tissue growth factor (CTGF) is widely thought to promote the development of fibrosis in collaboration with transforming growth factor (TGF)-β; however, most of the evidence for its involvement comes from correlative and culture-based studies. In this study, the importance of CTGF in tissue fibrosis was directly examined in three murine models of fibrotic disease: a novel model of multiorgan fibrosis induced by repeated intraperitoneal injections of CTGF and TGF-β2; the unilateral ureteral obstruction (UUO) renal fibrosis model; and an intratracheal bleomycin instillation model of pulmonary fibrosis.
  
  
  RESULTS
  Intraperitoneal coadministration of CTGF and TGF-β2 elicited a profound fibrotic response that was inhibited by the human anti-CTGF antibody FG-3019, as indicated by the ability of FG-3019 to ameliorate the histologic signs of fibrosis and reduce the otherwise increased hydroxyproline:proline (Hyp:Pro) ratios by 25% in kidney (P < 0.05), 30% in liver (P < 0.01) and 63% in lung (P < 0.05). Moreover, administration of either cytokine alone failed to elicit a fibrotic response, thus demonstrating that CTGF is both necessary and sufficient to initiate fibrosis in the presence of TGF-β and vice versa. In keeping with this requirement for CTGF function in fibrosis, FG-3019 also reduced the renal Hyp:Pro response up to 20% after UUO (P < 0.05). In bleomycin-injured animals, a similar trend towards a FG-3019 treatment effect was observed (38% reduction in total lung Hyp, P = 0.056). Thus, FG-3019 antibody treatment consistently reduced excessive collagen deposition and the pathologic severity of fibrosis in all models.
  
  
  CONCLUSIONS
  Cooperative interactions between CTGF and TGF-β signaling are required to elicit overt tissue fibrosis. This interdependence and the observed anti-fibrotic effects of FG-3019 indicate that anti-CTGF therapy may provide therapeutic benefit in different forms of fibroproliferative disease.
authors.affiliation: FibroGen Inc,, 409 Illinois St,, San Francisco, CA 94158, USA. tseeley@fibrogen.com.
authors.forename: Qingjian
authors.initials: Q
authors.lastname: Wang
authors.forename: William
authors.initials: W
authors.lastname: Usinger
authors.forename: Blake
authors.initials: B
authors.lastname: Nichols
authors.forename: Julia
authors.initials: J
authors.lastname: Gray
authors.forename: Leon
authors.initials: L
authors.lastname: Xu
authors.forename: Todd W
authors.initials: TW
authors.lastname: Seeley
authors.forename: Mitch
authors.initials: M
authors.lastname: Brenner
authors.forename: Guangjie
authors.initials: G
authors.lastname: Guo
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhang
authors.forename: Noelynn
authors.initials: N
authors.lastname: Oliver
authors.forename: Al
authors.initials: A
authors.lastname: Lin
authors.forename: David
authors.initials: D
authors.lastname: Yeowell