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Am J Pathol. Jan 1994; 144(1): 82–94.
PMCID: PMC1887110

Transforming growth factor-beta 1 stimulates glomerular mesangial cell synthesis of the 72-kd type IV collagenase.


Transforming growth factor-beta 1 (TGF-beta 1) is generally considered to exert positive effects on the accumulation of extracellular matrices. These occur as the net result of enhanced matrix protein synthesis, diminished matrix metalloproteinase (MMP) synthesis, and augmented production of specific inhibitors, including the tissue inhibitor of metalloproteinases (TIMP-1). Given that glomerular TGF-beta 1 synthesis is induced by inflammation, the effects of this cytokine on synthesis of the 72-kd type IV collagenase and TIMP-1 by cultured human mesangial cells were evaluated. Concentrations of TGF-beta 1 of 5 ng/ml and above specifically stimulated the synthesis of the 72-kd type IV collagenase. This effect was independent of the stimulatory effect of TGF-beta 1 on TIMP-1 synthesis, which was maximal in a lower concentration range (0.1 to 1 ng/ml). Most significantly, the net effect at the higher concentrations of TGF-beta 1 was an excess of enzyme over the TIMP-1 inhibitor. Northern blot analysis of TGF-beta 1-stimulated human mesangial cells demonstrated a specific increase in the abundance of the 3.1 kb mRNA transcript encoding the 72-kd type IV collagenase, presumably mediated by a direct stimulation of 72-kd type IV collagenase mRNA transcription observed as early as 3 hours after exposure to TGF-beta 1. These studies were extended to an analysis of the expression of TGF-beta 1 and 72-kd type IV collagenase mRNAs in normal and nephritic rats. In normal animals, basal TGF-beta 1 and 72-kd type IV collagenase mRNA expression was observed in a strictly mesangial distribution. After induction of acute immune complex-mediated glomerulonephritis, there was a major increase in TGF-beta 1 and 72-kd type IV collagenase mRNA expression, which was strictly limited to the expanded, hypercellular mesangial compartment. Enhanced synthesis of the mesangial type IV collagenase in response to TGF-beta 1 released during glomerular inflammatory processes could have an important role in the extensive glomerular matrix remodeling that accompanies these disorders.

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  • Border WA, Ruoslahti E. Transforming growth factor-beta 1 induces extracellular matrix formation in glomerulonephritis. Cell Differ Dev. 1990 Dec 2;32(3):425–431. [PubMed]
  • Border WA, Okuda S, Languino LR, Sporn MB, Ruoslahti E. Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1. Nature. 1990 Jul 26;346(6282):371–374. [PubMed]
  • Border WA, Okuda S, Languino LR, Ruoslahti E. Transforming growth factor-beta regulates production of proteoglycans by mesangial cells. Kidney Int. 1990 Feb;37(2):689–695. [PubMed]
  • Edwards DR, Murphy G, Reynolds JJ, Whitham SE, Docherty AJ, Angel P, Heath JK. Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO J. 1987 Jul;6(7):1899–1904. [PMC free article] [PubMed]
  • Ignotz RA, Endo T, Massagué J. Regulation of fibronectin and type I collagen mRNA levels by transforming growth factor-beta. J Biol Chem. 1987 May 15;262(14):6443–6446. [PubMed]
  • Kerr LD, Olashaw NE, Matrisian LM. Transforming growth factor beta 1 and cAMP inhibit transcription of epidermal growth factor- and oncogene-induced transin RNA. J Biol Chem. 1988 Nov 15;263(32):16999–17005. [PubMed]
  • Keski-Oja J, Raghow R, Sawdey M, Loskutoff DJ, Postlethwaite AE, Kang AH, Moses HL. Regulation of mRNAs for type-1 plasminogen activator inhibitor, fibronectin, and type I procollagen by transforming growth factor-beta. Divergent responses in lung fibroblasts and carcinoma cells. J Biol Chem. 1988 Mar 5;263(7):3111–3115. [PubMed]
  • Penttinen RP, Kobayashi S, Bornstein P. Transforming growth factor beta increases mRNA for matrix proteins both in the presence and in the absence of changes in mRNA stability. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1105–1108. [PMC free article] [PubMed]
  • Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH, et al. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4167–4171. [PMC free article] [PubMed]
  • Coimbra T, Wiggins R, Noh JW, Merritt S, Phan SH. Transforming growth factor-beta production in anti-glomerular basement membrane disease in the rabbit. Am J Pathol. 1991 Jan;138(1):223–234. [PMC free article] [PubMed]
  • Floege J, Johnson RJ, Gordon K, Iida H, Pritzl P, Yoshimura A, Campbell C, Alpers CE, Couser WG. Increased synthesis of extracellular matrix in mesangial proliferative nephritis. Kidney Int. 1991 Sep;40(3):477–488. [PubMed]
  • Davies M, Thomas GJ, Martin J, Lovett DH. The purification and characterization of a glomerular-basement-membrane-degrading neutral proteinase from rat mesangial cells. Biochem J. 1988 Apr 15;251(2):419–425. [PMC free article] [PubMed]
  • Johnson R, Yamabe H, Chen YP, Campbell C, Gordon K, Baker P, Lovett D, Couser WG. Glomerular epithelial cells secrete a glomerular basement membrane-degrading metalloproteinase. J Am Soc Nephrol. 1992 Mar;2(9):1388–1397. [PubMed]
  • Le Q, Shah S, Nguyen H, Cortez S, Baricos W. A novel metalloproteinase present in freshly isolated rat glomeruli. Am J Physiol. 1991 Apr;260(4 Pt 2):F555–F561. [PubMed]
  • Lovett DH, Sterzel RB, Kashgarian M, Ryan JL. Neutral proteinase activity produced in vitro by cells of the glomerular mesangium. Kidney Int. 1983 Feb;23(2):342–349. [PubMed]
  • Lovett DH, Johnson RJ, Marti HP, Martin J, Davies M, Couser WG. Structural characterization of the mesangial cell type IV collagenase and enhanced expression in a model of immune complex-mediated glomerulonephritis. Am J Pathol. 1992 Jul;141(1):85–98. [PMC free article] [PubMed]
  • Marti HP, McNeil L, Thomas G, Davies M, Lovett DH. Molecular characterization of a low-molecular-mass matrix metalloproteinase secreted by glomerular mesangial cells as PUMP-1. Biochem J. 1992 Aug 1;285(Pt 3):899–905. [PMC free article] [PubMed]
  • Martin J, Davies M, Thomas G, Lovett DH. Human mesangial cells secrete a GBM-degrading neutral proteinase and a specific inhibitor. Kidney Int. 1989 Nov;36(5):790–801. [PubMed]
  • Pollock AS, Lovett DH. Expression of phosphoenolpyruvate carboxykinase (PEPCK) chimeras in renal epithelial cells. Retention of appropriate physiological responsiveness using enhancerless retroviral vectors. Biochem J. 1992 Jun 15;284(Pt 3):725–732. [PMC free article] [PubMed]
  • Marti HP, McNeil L, Davies M, Martin J, Lovett DH. Homology cloning of rat 72 kDa type IV collagenase: cytokine and second-messenger inducibility in glomerular mesangial cells. Biochem J. 1993 Apr 15;291(Pt 2):441–446. [PMC free article] [PubMed]
  • Jaffer F, Saunders C, Shultz P, Throckmorton D, Weinshell E, Abboud HE. Regulation of mesangial cell growth by polypeptide mitogens. Inhibitory role of transforming growth factor beta. Am J Pathol. 1989 Aug;135(2):261–269. [PMC free article] [PubMed]
  • MacKay K, Striker LJ, Stauffer JW, Doi T, Agodoa LY, Striker GE. Transforming growth factor-beta. Murine glomerular receptors and responses of isolated glomerular cells. J Clin Invest. 1989 Apr;83(4):1160–1167. [PMC free article] [PubMed]
  • Overall CM, Wrana JL, Sodek J. Independent regulation of collagenase, 72-kDa progelatinase, and metalloendoproteinase inhibitor expression in human fibroblasts by transforming growth factor-beta. J Biol Chem. 1989 Jan 25;264(3):1860–1869. [PubMed]
  • Stetler-Stevenson WG, Brown PD, Onisto M, Levy AT, Liotta LA. Tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA expression in tumor cell lines and human tumor tissues. J Biol Chem. 1990 Aug 15;265(23):13933–13938. [PubMed]
  • Howard EW, Bullen EC, Banda MJ. Preferential inhibition of 72- and 92-kDa gelatinases by tissue inhibitor of metalloproteinases-2. J Biol Chem. 1991 Jul 15;266(20):13070–13075. [PubMed]
  • Firestein GS, Paine MM. Stromelysin and tissue inhibitor of metalloproteinases gene expression in rheumatoid arthritis synovium. Am J Pathol. 1992 Jun;140(6):1309–1314. [PMC free article] [PubMed]
  • Brown PD, Levy AT, Margulies IM, Liotta LA, Stetler-Stevenson WG. Independent expression and cellular processing of Mr 72,000 type IV collagenase and interstitial collagenase in human tumorigenic cell lines. Cancer Res. 1990 Oct 1;50(19):6184–6191. [PubMed]
  • Salo T, Lyons JG, Rahemtulla F, Birkedal-Hansen H, Larjava H. Transforming growth factor-beta 1 up-regulates type IV collagenase expression in cultured human keratinocytes. J Biol Chem. 1991 Jun 25;266(18):11436–11441. [PubMed]
  • Raghow R, Thompson JP. Molecular mechanisms of collagen gene expression. Mol Cell Biochem. 1989 Mar 16;86(1):5–18. [PubMed]
  • Fine A, Poliks CF, Smith BD, Goldstein RH. The accumulation of type I collagen mRNAs in human embryonic lung fibroblasts stimulated by transforming growth factor-beta. Connect Tissue Res. 1990;24(3-4):237–247. [PubMed]
  • Fine A, Poliks CF, Donahue LP, Smith BD, Goldstein RH. The differential effect of prostaglandin E2 on transforming growth factor-beta and insulin-induced collagen formation in lung fibroblasts. J Biol Chem. 1989 Oct 15;264(29):16988–16991. [PubMed]
  • Overall CM, Wrana JL, Sodek J. Transcriptional and post-transcriptional regulation of 72-kDa gelatinase/type IV collagenase by transforming growth factor-beta 1 in human fibroblasts. Comparisons with collagenase and tissue inhibitor of matrix metalloproteinase gene expression. J Biol Chem. 1991 Jul 25;266(21):14064–14071. [PubMed]
  • Kim SJ, Denhez F, Kim KY, Holt JT, Sporn MB, Roberts AB. Activation of the second promoter of the transforming growth factor-beta 1 gene by transforming growth factor-beta 1 and phorbol ester occurs through the same target sequences. J Biol Chem. 1989 Nov 15;264(32):19373–19378. [PubMed]
  • Ritzenthaler JD, Goldstein RH, Fine A, Lichtler A, Rowe DW, Smith BD. Transforming-growth-factor-beta activation elements in the distal promoter regions of the rat alpha 1 type I collagen gene. Biochem J. 1991 Nov 15;280(Pt 1):157–162. [PMC free article] [PubMed]
  • Riccio A, Pedone PV, Lund LR, Olesen T, Olsen HS, Andreasen PA. Transforming growth factor beta 1-responsive element: closely associated binding sites for USF and CCAAT-binding transcription factor-nuclear factor I in the type 1 plasminogen activator inhibitor gene. Mol Cell Biol. 1992 Apr;12(4):1846–1855. [PMC free article] [PubMed]
  • Tomooka S, Border WA, Marshall BC, Noble NA. Glomerular matrix accumulation is linked to inhibition of the plasmin protease system. Kidney Int. 1992 Dec;42(6):1462–1469. [PubMed]

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