title: Cell-cell contact activation of fibroblasts increases the expression of matrix metalloproteinases.
abstract: BACKGROUND
  We recently found that direct homotypic cell-cell contacts between human dermal fibroblasts induce a novel form of cell activation leading to non-apoptotic programmed cell death. As the major features of this process we identified massive induction of cyclo-oxygenase-2 and production of inflammatory prostaglandins. On the surface of the decomposing spheroids, activation of the major extracellular proteolytic cascade, plasminogen activation, associated with surface exposure of alpha-enolase, took place.
  
  
  OBJECTIVE
  To further characterize pericellular proteolysis by cell-cell contact-activated fibroblasts we studied the role of the other major extracellular proteolytic system, matrix metalloproteinases (MMPs).
  
  
  METHODS
  MMP expression in fibroblast clusters and monolayers was compared using mRNA microarrays and immunoblot analyses. The activities of MMPs were confirmed using MMP inhibitors and caseinolysis.
  
  
  RESULTS
  In microarrays MMP-1, -10, and -14 (MT1-MMP) were induced 5.8-, 106-, and 5.6-fold, respectively. These findings were confirmed by immunoblotting. Radial caseinolysis showed low level of proteolytic activity in spheroid-conditioned media; ilomastat, a general inhibitor of MMPs, suppressed 50% of the proteolytic activity thus confirming it to be at least in part due to MMPs. A cocktail of tetracycline-derived MMP inhibitors suppressed lactate dehydrogenase (LDH) release only 11%, and if combined with aprotinin 28%.
  
  
  CONCLUSIONS
  Cell-cell contact activation of fibroblasts induced MMP-1, -10, and MT1-MMP expression, suggesting similar signaling to that in inflammation and cancer.
authors.affiliation: Haartman Institute, University of Helsinki, Finland.
authors.forename: Vappu
authors.initials: V
authors.lastname: Sirén
authors.forename: Pertteli
authors.initials: P
authors.lastname: Salmenperä
authors.forename: Esko
authors.initials: E
authors.lastname: Kankuri
authors.forename: Jozef
authors.initials: J
authors.lastname: Bizik
authors.forename: Timo
authors.initials: T
authors.lastname: Sorsa
authors.forename: Taina
authors.initials: T
authors.lastname: Tervahartiala
authors.forename: Antti
authors.initials: A
authors.lastname: Vaheri
mesh_terms: D002450:Cell Communication / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053506:Matrix Metalloproteinase 10; D020782:Matrix Metalloproteinases / Q000276:immunology / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008648:Mesoderm / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010960:Plasminogen Activators / Q000378:metabolism; D018874:Spheroids, Cellular / Q000502:physiology
chemical_list: D010960:Plasminogen Activators; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D053506:Matrix Metalloproteinase 10; D020781:Matrix Metalloproteinase 1