title: Recombinant GPI-anchored TIMP-1 stimulates growth and migration of peritoneal mesothelial cells.
abstract: BACKGROUND
  Mesothelial cells are critical in the pathogenesis of post-surgical intraabdominal adhesions as well as in the deterioration of the peritoneal membrane associated with long-term peritoneal dialysis. Mesothelial denudation is a pathophysiolocigally important finding in these processes. Matrix metalloproteinase (MMP) biology underlies aspects of mesothelial homeostasis as well as wound repair. The endogenous tissue inhibitors of metalloproteinases (TIMPs) moderate MMP activity.
  
  
  RESULTS
  By modifying human TIMP-1 through the addition of a glycosylphosphatidylinositol (GPI) anchor, a recombinant protein was generated that efficiently focuses TIMP-1 on the cell surface. Treatment of primary mesothelial cells with TIMP-1-GPI facilitates their mobilization and migration leading to a dramatic increase in the rate of wound experimental closure. Mesothelial cells treated with TIMP-1-GPI showed a dose dependent increase in cell proliferation, reduced secretion of MMP-2, MMP-9, TNF-α and urokinase-type plasminogen activator (uPA), but increased tissue plasminogen activator (t-PA). Treatment resulted in reduced expression and processing of latent TGF-β1.
  
  
  CONCLUSIONS
  TIMP-1-GPI stimulated rapid and efficient in vitro wound closure. The agent enhanced mesothelial cell proliferation and migration and was bioactive in the nanogram range. The application of TIMP-1-GPI may represent a new approach for limiting or repairing damaged mesothelium.
authors.affiliation: Arbeitsgruppe Klinische Biochemie, Medizinische Klinik und Poliklinik IV, Universität München, Munich, Germany.
authors.forename: Roghieh
authors.initials: R
authors.lastname: Djafarzadeh
authors.forename: Matthias
authors.initials: M
authors.lastname: Sauter
authors.forename: Susan
authors.initials: S
authors.lastname: Notohamiprodjo
authors.forename: Elfriede
authors.initials: E
authors.lastname: Noessner
authors.forename: Pankaj
authors.initials: P
authors.lastname: Goyal
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Siess
authors.forename: Markus
authors.initials: M
authors.lastname: Wörnle
authors.forename: Andrea
authors.initials: A
authors.lastname: Ribeiro
authors.forename: Susanne
authors.initials: S
authors.lastname: Himmelein
authors.forename: Thomas
authors.initials: T
authors.lastname: Sitter
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Nelson
mesh_terms: D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004848:Epithelium / Q000187:drug effects / Q000254:growth & development*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects*; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008856:Microscopy, Fluorescence; D010537:Peritoneum / Q000166:cytology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D017261:Glycosylphosphatidylinositols; D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9