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Am J Pathol. Oct 1996; 149(4): 1287–1302.
PMCID: PMC1865201

Role of matrix metalloproteinases in failure to re-epithelialize after corneal injury.


Delayed re-epithelialization of the cornea after injury usually precedes stromal ulceration. Previous findings using a rat thermal injury model suggested that re-epithelialization is impeded by products of resident corneal cells, which destroy adhesive structures at the basement membrane zone. In this study, we provide additional evidence for this concept. Failure to re-epithelialize was found to correlate with an increase in the amounts of gelatinolytic matrix metalloproteinases present in the rat cornea. One of these gelatinases, gelatinase B, is synthesized by the resident corneal cells, and inhibitions of its synthesis correlated with inhibition of basement membrane dissolution. The matrix metalloproteinases collagenase and stromelysin are also synthesized by resident corneal cells in thermally injured corneas of rabbits, but the timing of bulk enzyme synthesis correlated more closely with deposition of repair tissue in the stroma than with failure to re-epithelialize. Nevertheless, in human corneas with repair defects, gelatinase B and collagenase are synthesized by cells in the basal layer of the epithelium directly adjacent to the basement membrane, suggesting that both could participate in dissolution of this structure. Importantly, treatment of thermally injured corneas with a synthetic inhibitor of matrix metalloproteinases significantly improved basement membrane integrity. These data support the concept that over-expression of matrix metalloproteinases by resident corneal cells impedes re-epithelialization after some types of corneal injury.

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  • Foster CS, Zelt RP, Mai-Phan T, Kenyon KR. Immunosuppression and selective inflammatory cell depletion. Studies on a guinea pig model of corneal ulceration after ocular alkali burning. Arch Ophthalmol. 1982 Nov;100(11):1820–1824. [PubMed]
  • Matsubara M, Zieske JD, Fini ME. Mechanism of basement membrane dissolution preceding corneal ulceration. Invest Ophthalmol Vis Sci. 1991 Dec;32(13):3221–3237. [PubMed]
  • Alexander CM, Werb Z. Proteinases and extracellular matrix remodeling. Curr Opin Cell Biol. 1989 Oct;1(5):974–982. [PubMed]
  • Fini ME, Girard MT. Expression of collagenolytic/gelatinolytic metalloproteinases by normal cornea. Invest Ophthalmol Vis Sci. 1990 Sep;31(9):1779–1788. [PubMed]
  • Fini ME, Girard MT. The pattern of metalloproteinase expression by corneal fibroblasts is altered by passage in cell culture. J Cell Sci. 1990 Oct;97(Pt 2):373–383. [PubMed]
  • Fini ME, Yue BY, Sugar J. Collagenolytic/gelatinolytic metalloproteinases in normal and keratoconus corneas. Curr Eye Res. 1992 Sep;11(9):849–862. [PubMed]
  • Matsubara M, Girard MT, Kublin CL, Cintron C, Fini ME. Differential roles for two gelatinolytic enzymes of the matrix metalloproteinase family in the remodelling cornea. Dev Biol. 1991 Oct;147(2):425–439. [PubMed]
  • Girard MT, Matsubara M, Kublin C, Tessier MJ, Cintron C, Fini ME. Stromal fibroblasts synthesize collagenase and stromelysin during long-term tissue remodeling. J Cell Sci. 1993 Apr;104(Pt 4):1001–1011. [PubMed]
  • Conn H, Berman M, Kenyon K, Langer R, Gage J. Stromal vascularization prevents corneal ulceration. Invest Ophthalmol Vis Sci. 1980 Apr;19(4):362–370. [PubMed]
  • Zieske JD, Bukusoglu G, Gipson IK. Enhancement of vinculin synthesis by migrating stratified squamous epithelium. J Cell Biol. 1989 Aug;109(2):571–576. [PMC free article] [PubMed]
  • Sakai LY, Keene DR, Morris NP, Burgeson RE. Type VII collagen is a major structural component of anchoring fibrils. J Cell Biol. 1986 Oct;103(4):1577–1586. [PMC free article] [PubMed]
  • Rousselle P, Lunstrum GP, Keene DR, Burgeson RE. Kalinin: an epithelium-specific basement membrane adhesion molecule that is a component of anchoring filaments. J Cell Biol. 1991 Aug;114(3):567–576. [PMC free article] [PubMed]
  • Heussen C, Dowdle EB. Electrophoretic analysis of plasminogen activators in polyacrylamide gels containing sodium dodecyl sulfate and copolymerized substrates. Anal Biochem. 1980 Feb;102(1):196–202. [PubMed]
  • Girard MT, Matsubara M, Fini ME. Transforming growth factor-beta and interleukin-1 modulate metalloproteinase expression by corneal stromal cells. Invest Ophthalmol Vis Sci. 1991 Aug;32(9):2441–2454. [PubMed]
  • Quinn CO, Scott DK, Brinckerhoff CE, Matrisian LM, Jeffrey JJ, Partridge NC. Rat collagenase. Cloning, amino acid sequence comparison, and parathyroid hormone regulation in osteoblastic cells. J Biol Chem. 1990 Dec 25;265(36):22342–22347. [PubMed]
  • Roswit WT, Halme J, Jeffrey JJ. Purification and properties of rat uterine procollagenase. Arch Biochem Biophys. 1983 Aug;225(1):285–295. [PubMed]
  • Lyons JG, Birkedal-Hansen B, Moore WG, O'Grady RL, Birkedal-Hansen H. Characteristics of a 95-kDa matrix metalloproteinase produced by mammary carcinoma cells. Biochemistry. 1991 Feb 12;30(6):1449–1456. [PubMed]
  • Blair HC, Teitelbaum SL, Ehlich LS, Jeffrey JJ. Collagenase production by smooth muscle: correlation of immunoreactive with functional enzyme in the myometrium. J Cell Physiol. 1986 Oct;129(1):111–123. [PubMed]
  • Saarialho-Kere UK, Kovacs SO, Pentland AP, Olerud JE, Welgus HG, Parks WC. Cell-matrix interactions modulate interstitial collagenase expression by human keratinocytes actively involved in wound healing. J Clin Invest. 1993 Dec;92(6):2858–2866. [PMC free article] [PubMed]
  • Saarialho-Kere UK, Chang ES, Welgus HG, Parks WC. Distinct localization of collagenase and tissue inhibitor of metalloproteinases expression in wound healing associated with ulcerative pyogenic granuloma. J Clin Invest. 1992 Nov;90(5):1952–1957. [PMC free article] [PubMed]
  • Saarialho-Kere UK, Pentland AP, Birkedal-Hansen H, Parks WC, Welgus HG. Distinct populations of basal keratinocytes express stromelysin-1 and stromelysin-2 in chronic wounds. J Clin Invest. 1994 Jul;94(1):79–88. [PMC free article] [PubMed]
  • Goldberg GI, Wilhelm SM, Kronberger A, Bauer EA, Grant GA, Eisen AZ. Human fibroblast collagenase. Complete primary structure and homology to an oncogene transformation-induced rat protein. J Biol Chem. 1986 May 15;261(14):6600–6605. [PubMed]
  • Wilhelm SM, Collier IE, Marmer BL, Eisen AZ, Grant GA, Goldberg GI. SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages. J Biol Chem. 1989 Oct 15;264(29):17213–17221. [PubMed]
  • Ståhle-Bäckdahl M, Parks WC. 92-kd gelatinase is actively expressed by eosinophils and stored by neutrophils in squamous cell carcinoma. Am J Pathol. 1993 Apr;142(4):995–1000. [PMC free article] [PubMed]
  • Grobelny D, Poncz L, Galardy RE. Inhibition of human skin fibroblast collagenase, thermolysin, and Pseudomonas aeruginosa elastase by peptide hydroxamic acids. Biochemistry. 1992 Aug 11;31(31):7152–7154. [PubMed]
  • Kurpakus MA, Stock EL, Jones JC. Analysis of wound healing in an in vitro model: early appearance of laminin and a 125 x 10(3) Mr polypeptide during adhesion complex formation. J Cell Sci. 1990 Aug;96(Pt 4):651–660. [PubMed]
  • Ando H, Twining SS, Yue BY, Zhou X, Fini ME, Kaiya T, Higginbotham EJ, Sugar J. MMPs and proteinase inhibitors in the human aqueous humor. Invest Ophthalmol Vis Sci. 1993 Dec;34(13):3541–3548. [PubMed]
  • Dohlman CH. The function of the corneal epithelium in health and disease. The Jonas S. Friedenwald Memorial Lecture. Invest Ophthalmol. 1971 Jun;10(6):383–407. [PubMed]
  • Gordon JM, Bauer EA, Eisen AZ. Collagenase in human cornea: immunologic localization. Arch Ophthalmol. 1980 Feb;98(2):341–345. [PubMed]
  • Kao WW, Ebert J, Kao CW, Covington H, Cintron C. Development of monoclonal antibodies recognizing collagenase from rabbit PMN; the presence of this enzyme in ulcerating corneas. Curr Eye Res. 1986 Nov;5(11):801–815. [PubMed]
  • Ståhle-Bäckdahl M, Inoue M, Guidice GJ, Parks WC. 92-kD gelatinase is produced by eosinophils at the site of blister formation in bullous pemphigoid and cleaves the extracellular domain of recombinant 180-kD bullous pemphigoid autoantigen. J Clin Invest. 1994 May;93(5):2022–2030. [PMC free article] [PubMed]
  • Saarialho-Kere UK, Crouch EC, Parks WC. Matrix metalloproteinase matrilysin is constitutively expressed in adult human exocrine epithelium. J Invest Dermatol. 1995 Aug;105(2):190–196. [PubMed]
  • Bazan HE, Tao Y, Bazan NG. Platelet-activating factor induces collagenase expression in corneal epithelial cells. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8678–8682. [PMC free article] [PubMed]
  • Fini ME, Strissel KJ, Girard MT, Mays JW, Rinehart WB. Interleukin 1 alpha mediates collagenase synthesis stimulated by phorbol 12-myristate 13-acetate. J Biol Chem. 1994 Apr 15;269(15):11291–11298. [PubMed]
  • Hasty KA, Pourmotabbed TF, Goldberg GI, Thompson JP, Spinella DG, Stevens RM, Mainardi CL. Human neutrophil collagenase. A distinct gene product with homology to other matrix metalloproteinases. J Biol Chem. 1990 Jul 15;265(20):11421–11424. [PubMed]
  • Freije JM, Díez-Itza I, Balbín M, Sánchez LM, Blasco R, Tolivia J, López-Otín C. Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas. J Biol Chem. 1994 Jun 17;269(24):16766–16773. [PubMed]
  • Henriet P, Rousseau GG, Eeckhout Y. Cloning and sequencing of mouse collagenase cDNA. Divergence of mouse and rat collagenases from the other mammalian collagenases. FEBS Lett. 1992 Sep 28;310(2):175–178. [PubMed]
  • Burns FR, Gray RD, Paterson CA. Inhibition of alkali-induced corneal ulceration and perforation by a thiol peptide. Invest Ophthalmol Vis Sci. 1990 Jan;31(1):107–114. [PubMed]
  • Schultz GS, Strelow S, Stern GA, Chegini N, Grant MB, Galardy RE, Grobelny D, Rowsey JJ, Stonecipher K, Parmley V, et al. Treatment of alkali-injured rabbit corneas with a synthetic inhibitor of matrix metalloproteinases. Invest Ophthalmol Vis Sci. 1992 Nov;33(12):3325–3331. [PubMed]
  • Falanga V. Chronic wounds: pathophysiologic and experimental considerations. J Invest Dermatol. 1993 May;100(5):721–725. [PubMed]
  • Grinnell F, Ho CH, Wysocki A. Degradation of fibronectin and vitronectin in chronic wound fluid: analysis by cell blotting, immunoblotting, and cell adhesion assays. J Invest Dermatol. 1992 Apr;98(4):410–416. [PubMed]
  • Wysocki AB, Staiano-Coico L, Grinnell F. Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol. 1993 Jul;101(1):64–68. [PubMed]

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