This Article Order Full text via Infotrieve Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Theret, N. Articles by Clement, B. Search for Related Content PubMed PubMed Citation Articles by Theret, N. Articles by Clement, B.

American Journal of Pathology, Vol 150, 51-58, Copyright © 1997 by American Society for Investigative Pathology

REGULAR ARTICLES

Activation of matrix metalloproteinase-2 from hepatic stellate cells requires interactions with hepatocytes

N Theret, O Musso, A L'Helgoualc'h and B Clement
Detoxication and Tissue Repair Unit INSERM, U-456, Rennes I University School of Medicine, France.

Activation of matrix metalloproteinase (MMP)-2, the 72-kd collagenase IV/gelatinase A, is involved in extracellular matrix remodeling. It has been suggested that a membrane-type MMP (MT-MMP-1) and the tissue inhibitor of metalloproteinase (TIMP)-2 are involved in MMP-2 processing, but the exact mechanism(s) of its activation remains unclear. We have investigated the role of cell-cell cooperation in the activation of pro-MMP-2 in the liver, using pure cultures and co- cultures of hepatocytes and hepatic stellate cells (HSCs). Northern blot analysis and in situ hybridization showed that, in both pure and co-cultures, HSCs, but not hepatocytes, expressed MMP-2, TIMP-2, and MT- MMP-1 mRNA. Zymography analyses revealed the latent form of MMP-2 in medium from 2-day-old pure HSC cultures with higher amounts in medium from hepatocyte/HSC co-cultures. When hepatocytes were added to 10-day- old HSC cultures, the activated form of MMP-2 was detected, concomitantly with the deposition of an abundant extracellular matrix. Incubation of plasma membrane-enriched fractions from hepatocytes with conditioned medium from pure HSC cultures generated the activated species of MMP-2 (62 and 59 kd). Activation of pro-MMP-2 by hepatocyte membranes was inhibited by EDTA, heat, and trypsin but not by serine proteinase inhibitors. These data show that the co-expression of TIMP- 2, MMP-2, and MT-MMP-1 by HSCs does not lead to secretion of the activated form of MMP-2. Hepatocytes, which do not express MMP-2, TIMP- 2, or MT-MMP-1, induce MMP-2 activation through a plasma membrane- dependent mechanism(s), thus suggesting that cell-cell interactions are involved in this process in vivo.

This article has been cited by other articles:

				F. Marongiu, S. Doratiotto, S. Montisci, P. Pani, and E. Laconi Liver Repopulation and Carcinogenesis: Two Sides of the Same Coin? Am. J. Pathol., April 1, 2008; 172(4): 857 - 864. [Abstract] [Full Text] [PDF]

				S. L. Friedman Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver Physiol Rev, January 1, 2008; 88(1): 125 - 172. [Abstract] [Full Text] [PDF]

				E. Lechapt-Zalcman, V. Pruliere-Escabasse, D. Advenier, S. Galiacy, C. Charriere-Bertrand, A. Coste, A. Harf, M.-P. d'Ortho, and E. Escudier Transforming growth factor-beta1 increases airway wound repair via MMP-2 upregulation: a new pathway for epithelial wound repair? Am J Physiol Lung Cell Mol Physiol, June 1, 2006; 290(6): L1277 - L1282. [Abstract] [Full Text] [PDF]

				A. Mazzocca, S. C. Sciammetta, V. Carloni, L. Cosmi, F. Annunziato, T. Harada, S. Abrignani, and M. Pinzani Binding of Hepatitis C Virus Envelope Protein E2 to CD81 Up-regulates Matrix Metalloproteinase-2 in Human Hepatic Stellate Cells J. Biol. Chem., March 25, 2005; 280(12): 11329 - 11339. [Abstract] [Full Text] [PDF]

				C. Strup-Perrot, D. Mathe, C. Linard, D. Violot, F. Milliat, A. Francois, J. Bourhis, and M.-C. Vozenin-Brotons Global gene expression profiles reveal an increase in mRNA levels of collagens, MMPs, and TIMPs in late radiation enteritis Am J Physiol Gastrointest Liver Physiol, October 1, 2004; 287(4): G875 - G885. [Abstract] [Full Text] [PDF]

				A. E. Kossakowska, D. R. Edwards, S. S. Lee, L. S. Urbanski, A. L. Stabbler, C.-L. Zhang, B. W. Phillips, Y. Zhang, and S. J. Urbanski Altered Balance Between Matrix Metalloproteinases and Their Inhibitors in Experimental Biliary Fibrosis Am. J. Pathol., December 1, 1998; 153(6): 1895 - 1902. [Abstract] [Full Text] [PDF]

				N. Theret, O. Musso, A. L'Helgoualc'h, J.-P. Campion, and B. Clement Differential Expression and Origin of Membrane-Type 1 and 2 Matrix Metalloproteinases (MT-MMPs) in Association with MMP2 Activation in Injured Human Livers Am. J. Pathol., September 1, 1998; 153(3): 945 - 954. [Abstract] [Full Text] [PDF]