Differential expression of extracellular matrix metalloproteinase inducer (CD147) in normal and ulcerated corneas: role in epithelio-stromal interactions and matrix metalloproteinase induction.
Extracellular matrix metalloproteinase inducer (EMMPRIN) was originally identified on the tumor cell surface as an inducer of matrix metalloproteinase (MMP) production in neighboring fibroblasts. Here we demonstrate a role for EMMPRIN in MMP induction during corneal wound healing. MMP and EMMPRIN expression was analyzed in normal and ulcerated human corneas, as well as in corneal epithelial and stromal cells in culture using confocal microscopy, zymography, immunoblots, and real-time polymerase chain reaction. In normal cornea EMMPRIN was predominantly expressed in the epithelium but was markedly induced in the anterior stroma of ulcerated corneas. This coincided with MMP-2 induction that co-localized with EMMPRIN at the epithelio-stromal boundary. The role of epithelial-stromal interaction in MMP induction was investigated in an in vitro co-culture system and demonstrated an induction and co-localization of EMMPRIN and MMP-2 in the fibroblasts at the interface with epithelial cells. Direct contact of fibroblasts with EMMPRIN-containing purified epithelial cell membranes also induced MMP-1, MMP-2, and EMMPRIN and this was inhibited by a blocking anti-EMMPRIN antibody, suggesting that EMMPRIN was primarily responsible for this induction. These findings, and the up-regulation of EMMPRIN by epidermal growth factor and transforming growth factor-beta, demonstrate a role for EMMPRIN in wound healing and suggest that sustained local up-regulation of EMMPRIN and MMPs in chronic situations in which healing is delayed may lead to excessive matrix degradation and corneal melts.
Gabison
Eric E
EE
Institut de Recherche sur la Peau, Hôpital St. Louis, INSERM U 532, 1 Avenue Claude Vellefaux, 75010 Paris, France. egabison@wanadoo.fr
Mourah
Samia
S
Steinfels
Emanuelle
E
Yan
Li
L
Hoang-Xuan
Thanh
T
Watsky
Mitchel A
MA
De Wever
Bart
B
Calvo
Fabien
F
Mauviel
Alain
A
Menashi
Suzanne
S
D015703:Antigens, CD / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000235:genetics*; D051926:Basigin; D002460:Cell Line; D002772:Cholera Toxin / Q000494:pharmacology; D018920:Coculture Techniques; D003315:Cornea / Q000166:cytology / Q000276:immunology*; D003320:Corneal Ulcer / Q000276:immunology* / Q000473:pathology; D017931:DNA Primers; D004815:Epidermal Growth Factor / Q000494:pharmacology; D019573:Epithelium, Corneal / Q000166:cytology / Q000276:immunology / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000494:pharmacology; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction; D012016:Reference Values; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
D015703:Antigens, CD; D000951:Antigens, Neoplasm; C497886:BSG protein, human; D017931:DNA Primers; D007328:Insulin; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D051926:Basigin; D004815:Epidermal Growth Factor; D002772:Cholera Toxin