title: 2-Methoxyestradiol inhibits bleomycin-induced systemic sclerosis through suppression of fibroblast activation.
abstract: BACKGROUND
  The most dominant feature of systemic sclerosis (SSc) is fibrosis, which is caused by overproduction of collagen by fibroblasts. 2-Methoxyestradiol (2-ME) has exhibited disease-modifying activity in animal models of rheumatoid arthritis and autoimmune encephalomyelitis and inhibitory effect in cell proliferation and collagen synthesis. Therefore, we hypothesized that 2-ME may exhibit antifibrotic effect in SSc.
  
  
  OBJECTIVE
  To investigate the antifibrotic effect of 2-ME in SSc.
  
  
  METHODS
  We established a bleomycin-induced SSc mice model by injection with bleomycin daily for 21 days. 2-ME (100mg/kg/d) was simultaneously administered for 14 days. On the end of Week1 (W1), W2, W3 and W4, skins and lungs were collected for histological examination and analysis of hydroxyproline content and mRNA level of α1(I) procollagen (COL1A1) and COL1A2. In skin fibroblasts derived from SSc patients and healthy subjects treated with 2-ME (1, 5, or 25 μM), we examined cell proliferation, expression of α-smooth muscle actin (SMA) and mRNA level of COL1A1, COL1A2, COL3A1, matrix metalloproteinase(MMP)-1 and tissue inhibitors of MMP (TIMP)-1.
  
  
  RESULTS
  We found reduced dermal thickness and lung fibrosis and decreased hydroxyproline content and mRNA level of COL1A1 and COL1A2 in skin and lung in SSc mice treated with 2-ME. In cell study, we observed a dose- and time-dependent inhibitory effect on proliferation of SSc fibroblasts by 2-ME. We also detected reduced α-SMA expression, decreased mRNA level of COL1A1, COL1A2, COL3A1 and TIMP-1, and increased mRNA level of MMP-1 in SSc fibroblasts treated with 2-ME.
  
  
  CONCLUSIONS
  2-ME could suppress SSc tissue fibrosis, which may be attributable to its inhibitory effect on the excessive proliferation, differentiation and production of collagen in fibroblasts. 2-ME is rising as a prospective agent for control of fibrosis in SSc.
authors.affiliation: Department of Dermatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
authors.forename: Lubing
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Dermatology, Wuhan No.1 Hospital, Wuhan, 430022, China.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Dermatology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. Electronic address: li.ming@zs-hospital.sh.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
mesh_terms: D000077584:2-Methoxyestradiol; D000293:Adolescent; D000328:Adult; D000818:Animals; D001761:Bleomycin / Q000009:adverse effects*; D002454:Cell Differentiation; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D012333:RNA, Messenger; D001761:Bleomycin; D004958:Estradiol; D000077584:2-Methoxyestradiol; D003094:Collagen; D006909:Hydroxyproline
keywords: 2-Methoxyestradiol; Collagen; Fibroblast; Fibrosis; Systemic sclerosis