title: TIMP-1 Induces α-Smooth Muscle Actin in Fibroblasts to Promote Urethral Scar Formation.
abstract: OBJECTIVE
  Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been reported to upregulate in urethral scar. However, the underlying molecular mechanisms remain undefined.
  
  
  METHODS
  Here, we studied levels of TIMP-1 and α-smooth muscle actin (α-SMA) in the fibroblasts isolated from urethral scar tissues, compared to the fibroblasts isolated from normal urethra. Then we either overexpressed TIMP-1, or inhibited TIMP-1 by lentiviruses carrying a transgene or a short hairpin small interfering RNA for TIMP-1 in human fibroblasts. We examined the effects of modulation of TIMP-1 on α-SMA, and on epithelial-mesenchymal transition (EMT)-related genes. We also studied the underlying mechanisms.
  
  
  RESULTS
  We detected significantly higher levels of TIMP-1 and α-smooth muscle actin (α-SMA) in the fibroblasts isolated from urethral scar tissues, compared to the fibroblasts isolated from normal urethra. Moreover, the levels of TIMP-1 and α-SMA strongly correlated. Moreover, we found that TIMP-1 significantly increased levels of α-SMA, transforming growth factor β 1 (TGFβ1), Collagen I and some other key factors related to an enhanced EMT, suggesting that TIMP-1 may induce transformation of fibroblasts into myofibroblasts to promote tissue EMT to enhance the formation of urethral scar. Moreover, increases in TIMP-1 also induced an increase in fibroblast cell growth and cell invasion, in an ERK/MAPK-signaling-dependent manner.
  
  
  CONCLUSIONS
  Our study thus highlights a pivotal role of TIMP-1 in urethral scar formation.
authors.affiliation: Department of Urology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Yinglong
authors.initials: Y
authors.lastname: Sa
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.forename: Hongbin
authors.initials: H
authors.lastname: Li
authors.forename: Hailin
authors.initials: H
authors.lastname: Guo
mesh_terms: D000199:Actins / Q000378:metabolism*; D002921:Cicatrix / Q000378:metabolism* / Q000503:physiopathology; D024042:Collagen Type I / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D006801:Humans; D058628:Myofibroblasts / Q000378:metabolism* / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014521:Urethra / Q000378:metabolism* / Q000503:physiopathology
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D024042:Collagen Type I; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1