title: Exogenous bone morphogenetic protein-7 reduces hepatic fibrosis in Schistosoma japonicum-infected mice via transforming growth factor-β/Smad signaling.
abstract: OBJECTIVE
  To investigate the antifibrotic effects of bone morphogenetic protein-7 (BMP-7) on Schistosoma japonicum (S. japonicum)-induced hepatic fibrosis in BALB/C mice.
  
  
  METHODS
  Sixty BALB/C mice were randomly divided into three groups, including a control group (group A, n = 20), model group (group B, n = 20) and BMP-7 treated group (group C, n = 20). The mice in group B and group C were abdominally infected with S. japonicum cercariae to induce a schistosomal hepatic fibrosis model. The mice in group C were administered human recombinant BMP-7. Liver samples were extracted from mice sacrificed at 9 and 15 wk after modeling. Hepatic histopathological changes were assessed using Masson's staining. Transforming growth factor-beta 1 (TGF-β1), alpha-smooth muscle actin (α-SMA), phosphorylated Smad2/3 (pSmad2/3) and Smad7 protein levels and localization were measured by Western blotting and immunohistochemistry, respectively, and their mRNA expressions were detected by reverse transcription-polymerase chain reaction (RT-PCR).
  
  
  RESULTS
  The schistosomal hepatic fibrosis mouse model was successfully established, as the livers of mice in group B and group C showed varying degrees of typical schistosomal hepatopathologic changes such as egg granuloma and collagen deposition. The degree of collagen deposition in group C was higher than that in group A (week 9: 22.95 ± 6.66 vs 2.02 ± 0.76; week 15: 12.84 ± 4.36 vs 1.74 ± 0.80; P < 0.05), but significantly lower than that in group B (week 9: 22.95 ± 6.66 vs 34.43 ± 6.96; week 15: 12.84 ± 4.36 vs 18.90 ± 5.07; P < 0.05) at both time points. According to immunohistochemistry data, the expressions of α-SMA, TGF-β1 and pSmad2/3 protein in group C were higher than those in group A (α-SMA: week 9: 21.24 ± 5.73 vs 0.33 ± 0.20; week 15: 12.42 ± 4.88 vs 0.34 ± 0.27; TGF-β1: week 9: 37.00 ± 13.74 vs 3.73 ± 2.14; week 15: 16.71 ± 9.80 vs 3.08 ± 2.35; pSmad2/3: week 9: 12.92 ± 4.81 vs 0.83 ± 0.48; week 15: 7.87 ± 4.09 vs 0.90 ± 0.45; P < 0.05), but significantly lower than those in group B (α-SMA: week 9: 21.24 ± 5.73 vs 34.39 ± 5.74; week 15: 12.42 ± 4.88 vs 25.90 ± 7.01; TGF-β1: week 9: 37.00 ± 13.74 vs 55.66 ± 14.88; week 15: 16.71 ± 9.80 vs 37.10 ± 12.51; pSmad2/3: week 9: 12.92 ± 4.81 vs 19.41 ± 6.87; week 15: 7.87 ± 4.09 vs 13.00 ± 4.98; P < 0.05) at both time points; the expression of Smad7 protein in group B was higher than that in group A and group C at week 9 (8.46 ± 3.95 vs 1.00 ± 0.40 and 8.46 ± 3.95 vs 0.77 ± 0.42; P < 0.05), while there were no differences in Smad7 expression between the three groups at week 15 (1.09 ± 0.38 vs 0.97 ± 0.42 vs 0.89 ± 0.39; P > 0.05). Although minor discrepancies were observed, the results of RT-PCR and Western blotting were mainly consistent with the immunohistochemical results.
  
  
  CONCLUSIONS
  Exogenous BMP-7 significantly decreased the degree of hepatic fibrosis in both the acute and chronic stages of hepato-schistosomiasis, and the regulatory mechanism may involve the TGF-β/Smad signaling pathway.
authors.affiliation: Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China.
authors.forename: Bo-Lin
authors.initials: BL
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Peng
authors.forename: Qing-Fu
authors.initials: QF
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000469:parasitology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage; D012549:Schistosoma japonicum / Q000472:pathogenicity*; D012554:Schistosomiasis japonica / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D012333:RNA, Messenger; D011994:Recombinant Proteins; D051785:Smad Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1
keywords: BALB/C mice; Bone morphogenetic protein-7; Hepatic fibrosis; Schistosoma japonicum; Smad
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