title: Dysregulated proteolytic balance as the basis of excess extracellular matrix in fibrotic disease.
abstract: To investigate mechanisms of tissue fibrosis, we developed a model of ovine fetal bladder fibrosis due to surgically induced obstruction. Tissues were analyzed for matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Active MMP-2 was not detected in obstructed bladders, while latent and active forms were detected in normal bladders. MMP-1 (interstitial collagenase) activity was lower in obstructed bladders. MMP inhibitory activity was increased with obstruction, as were levels of TIMP mRNA and protein. These results indicate that the proteins responsible for collagen degradation are present in the developing bladder, and a shift in the proteolytic balance favoring inhibition of degradation occurs in a model of obstruction-induced fibrosis. This altered proteolytic balance favors accumulation of extracellular matrix and decreased tissue compliance characteristic of this and perhaps other fibrotic conditions.
authors.affiliation: Department of Urology, Children's Hospital, Boston, Massachusetts, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Peters
authors.forename: M R
authors.initials: MR
authors.lastname: Freeman
authors.forename: C A
authors.initials: CA
authors.lastname: Fernandez
authors.forename: J
authors.initials: J
authors.lastname: Shepard
authors.forename: D G
authors.initials: DG
authors.lastname: Wiederschain
authors.forename: M A
authors.initials: MA
authors.lastname: Moses
mesh_terms: D000818:Animals; D017364:Collagenases / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005333:Fetus / Q000378:metabolism; D005355:Fibrosis; D018093:Gelatinases / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D020781:Matrix Metalloproteinase 1; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012016:Reference Values; D012756:Sheep / Q000196:embryology; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases; D001743:Urinary Bladder / Q000378:metabolism* / Q000473:pathology*; D001748:Urinary Bladder Neck Obstruction / Q000378:metabolism / Q000473:pathology
chemical_list: D006023:Glycoproteins; D011506:Proteins; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D010447:Peptide Hydrolases; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1