title: Transforming growth factor-beta is a potent inhibitor of extracellular matrix degradation by cultured human mesangial cells.
abstract: Accumulation of the glomerular extracellular matrix (ECM) is a pivotal event in the progression from acute glomerular injury to end-stage renal disease. Although enhanced ECM synthesis has been demonstrated to contribute to ECM accumulation, the role of decreased ECM degradation is largely unknown. It was previously shown that glomerular ECM degradation is mediated by a plasminogen activator (PA)/plasmin/matrix metalloproteinase 2 (MMP-2) cascade. However, little information is available regarding the factors that regulate the activity of this degradative cascade in normal or pathologic states. Transforming growth factor-beta1 (TGF-beta1) is shown here to be a potent inhibitor of ECM degradation by cultured human mesangial cells. Using human mesangial cells grown on thin films of 125I-labeled Matrigel, dose-dependent inhibition of ECM degradation in the presence of TGF-beta1 was observed, reaching >90% inhibition with 0.4 ng/ml TGF-beta1. Addition of anti-TGF-beta antibodies (4 microg/ml) in the absence of exogenous TGF-beta increased ECM degradation (1.8+/-0.2-fold versus controls, P<0.05). In contrast, platelet-derived growth factor, at concentrations up to 10 ng/ml, had no effect on ECM degradation. TGF-beta completely blocked the conversion of plasminogen to plasmin and markedly reduced the conversion of latent MMP-2 to active MMP-2. TGF-beta did not significantly alter the levels of tissue PA, total MMP-2, or tissue inhibitor of metalloproteinase-1, but did increase the levels of PA inhibitor- (1.8-fold, P<0.05), the major physiologic inhibitor of PA. These data document that TGF-beta is a potent inhibitor of ECM degradation by cultured human mesangial cells, and they suggest that decreased mesangial matrix degradation, caused by TGF-beta-mediated decreases in the activity of the PA/plasmin/MMP-2 cascade, may contribute to the glomerular matrix accumulation that occurs in progressive renal disease.
authors: Department of Biochemistry, Tulane Medical School, New Orleans, Louisiana 70112, USA. baricosw@mailhost.tcs.tulane.edu
authors: W H
authors: WH
authors: Baricos
authors: S L
authors: SL
authors: Cortez
authors: M
authors: M
authors: Deboisblanc
authors: S
authors: S
authors: Xin
mesh_terms: D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D017364:Collagenases / Q000032:analysis; D003470:Culture Media / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D020781:Matrix Metalloproteinase 1; D008666:Metalloendopeptidases / Q000032:analysis; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology; D012016:Reference Values; D010959:Tissue Plasminogen Activator / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis
chemical_list: D003470:Culture Media; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D017364:Collagenases; D008666:Metalloendopeptidases; D020781:Matrix Metalloproteinase 1