HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend 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 Daniels, J. T. Articles by Khaw, P. T. Search for Related Content PubMed PubMed Citation Articles by Daniels, J. T. Articles by Khaw, P. T.

Human Corneal Epithelial Cells Require MMP-1 for HGF-Mediated Migration on Collagen I

¹From the Wound Healing Research Unit, Division of Pathology, and the ²Division of Cell Biology, Institute of Ophthalmology, London, United Kingdom; the ³Department of Dermatology and Venereology, University of Helsinki, Helsinki, Finland; the ⁴School of Biological Sciences, University of East Anglia, Norwich, United Kingdom; and ⁵Moorfields Eye Hospital National Health Service Trust, London, United Kingdom.

PURPOSE. To investigate the potential regulation of matrix metalloproteinases (MMPs) by hepatocyte growth factor (HGF), and to identify individual MMPs essential for migration of human corneal epithelial cells.

METHODS. Migration of human corneal epithelial cells (HCECs) was measured with a colony dispersion assay in response to concentrations of HGF (0–50 ng/mL). MMP activity in the conditioned media collected from the dispersion assay was assessed by zymography. The broad-spectrum MMP inhibitor ilomastat (1–100 µM) or an MMP-9–neutralizing antibody (1–10 µg/mL) were included in the dispersion assay to determine their effects on HCEC migration. Immunocytochemistry and in situ hybridization were used to localize MMP-1 in HCECs in the colony dispersion assay and in a human ex vivo corneal wound-healing model, respectively. ELISA for MMP-1 was performed on conditioned medium from migrating HCECs. Neutralizing antibodies to MMP-1 and -9 were added to an in vitro scratch-wound model to assess the effect on HCEC healing.

RESULTS. HCEC migration (P < 0.05) and MMP-2 and -9 released into the medium increased in response to HGF in a dose-dependent manner up to 20 ng/mL. Broad-spectrum MMP inhibition significantly reduced HCEC migration (P < 0.05). In contrast, neutralization of MMP-9 increased migration (P < 0.05). MMP-1 was found in association with HCECs at the migratory leading edge in both the dispersion and the ex vivo wound-healing experiments, and was found to be stimulated above basal levels by HGF. Neutralization of MMP-1 significantly decreased (P < 0.05), whereas neutralization of MMP-9 significantly increased (P < 0.05), scratch-wound closure.

CONCLUSIONS. This study provided novel data regarding HCEC migration in response to HGF and highlighted the importance of MMPs, particularly MMP-1 in migration and possibly reepithelialization in vivo. MMP-9 and/or -2 may be released by HCECs to remodel matrix behind the leading migratory front. Studies such as this are essential to assist in the safe and efficacious design of MMP inhibitors for therapeutic use in the eye.

This article has been cited by other articles:

				S. Pegorier, L. A. Wagner, G. J. Gleich, and M. Pretolani Eosinophil-Derived Cationic Proteins Activate the Synthesis of Remodeling Factors by Airway Epithelial Cells J. Immunol., October 1, 2006; 177(7): 4861 - 4869. [Abstract] [Full Text] [PDF]

				S. Goda, H. Inoue, H. Umehara, M. Miyaji, Y. Nagano, N. Harakawa, H. Imai, P. Lee, J. B. MaCarthy, T. Ikeo, et al. Matrix Metalloproteinase-1 Produced by Human CXCL12-Stimulated Natural Killer Cells Am. J. Pathol., August 1, 2006; 169(2): 445 - 458. [Abstract] [Full Text] [PDF]

				W. Han, M. K. H. Yap, J. Wang, and S. P. Yip Family-Based Association Analysis of Hepatocyte Growth Factor (HGF) Gene Polymorphisms in High Myopia. Invest. Ophthalmol. Vis. Sci., June 1, 2006; 47(6): 2291 - 2299. [Abstract] [Full Text] [PDF]

				L. Liu, D. Hartwig, S. Harloff, P. Herminghaus, T. Wedel, K. Kasper, and G. Geerling Corneal epitheliotrophic capacity of three different blood-derived preparations. Invest. Ophthalmol. Vis. Sci., June 1, 2006; 47(6): 2438 - 2444. [Abstract] [Full Text] [PDF]

				M. Ueno, B. L. Lyons, L. M. Burzenski, B. Gott, D. J. Shaffer, D. C. Roopenian, and L. D. Shultz Accelerated Wound Healing of Alkali-Burned Corneas in MRL Mice Is Associated with a Reduced Inflammatory Signature Invest. Ophthalmol. Vis. Sci., November 1, 2005; 46(11): 4097 - 4106. [Abstract] [Full Text] [PDF]

				M. Saghizadeh, A. A. Kramerov, J. Tajbakhsh, A. M. Aoki, C. Wang, N.-N. Chai, J. Y. Ljubimova, T. Sasaki, G. Sosne, M. R. J. Carlson, et al. Proteinase and Growth Factor Alterations Revealed by Gene Microarray Analysis of Human Diabetic Corneas Invest. Ophthalmol. Vis. Sci., October 1, 2005; 46(10): 3604 - 3615. [Abstract] [Full Text] [PDF]

				G. A. Limb, K. Matter, G. Murphy, A. D. Cambrey, P. N. Bishop, G. E. Morris, and P. T. Khaw Matrix Metalloproteinase-1 Associates with Intracellular Organelles and Confers Resistance to Lamin A/C Degradation during Apoptosis Am. J. Pathol., May 1, 2005; 166(5): 1555 - 1563. [Abstract] [Full Text] [PDF]

				E. E. Gabison, S. Mourah, E. Steinfels, L. Yan, T. Hoang-Xuan, M. A. Watsky, B. De Wever, F. Calvo, A. Mauviel, and S. Menashi Differential Expression of Extracellular Matrix Metalloproteinase Inducer (CD147) in Normal and Ulcerated Corneas: Role in Epithelio-Stromal Interactions and Matrix Metalloproteinase Induction Am. J. Pathol., January 1, 2005; 166(1): 209 - 219. [Abstract] [Full Text] [PDF]