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Eric E. Gabison, Eric Huet, Benoit Vallée, Christophe Baudouin, Isabelle Cochereau, Suzanne Menashi; Role Of The Matrix Metalloproteinase Inducer Cd147/emmprin In Myofibroblasts Differentiation : Consequences In Extracellular Matrix Remodeling. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2532.
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Extracellular matrix metalloproteinase inducer (EMMPRIN) is a cell surface glycoprotein enriched on tumor cells and present in normal epithelia. It is mainly known for its ability to induce matrix metalloproteinase production in fibroblasts following direct epithelial-stromal interaction. We recently have presented evidence that EMMPRIN, in addition to inducing proteases production, can also actively participate in the process of myofibroblasts differentiation. We investigated the differential effects of TGFb, EMMPRIN and IL1 on corneal fibroblast differentiation and on the collagenolytic balance in vitro. Additionally, we investigated the phenotype of corneal fibroblasts following injury in vivo in EMMPRIN deficient and wild type mice.
Comparative studies were conducted on HTK corneal fibroblasts to analyze the effect of EMMPRIN, TGFβ and IL1 on the regulation of MMPs, uPA, TIMPs, αSMA and type I collagen. Expression of αSMA was analyzed by Western blot of the cell lysate, MMP-1, -2 and uPA were quantified in the conditioned medium by Western blot; gelatin zymography and by casein plaminogen zymography respectively; TIMPs were quantified by reversed gelatin zymography. Additionally, photorefractive keratectomy (PRK) and corneal penetrating injuries were performed in EMMPRIN deficient and wild type mice and αSMA postitive cells were detected by confoncal immunohistochemistry.
Both TGFβ and IL1 upregulated EMMPRIN expression in corneal fibroblasts, while only TGFβ and EMMPRIN increased their αSMA expression. EMMPRIN and IL1 treatment was associated with MMP-1 induction while TGFβ was associated with an inhibition of the protease expression and an induction of TIMP-1 and Type I collagen. Furthermore, EMMPRIN greatly increased the expression of the urokinase type plasminogen activator (uPA) in corneal fibroblasts. Following PRK, EMMPRIN deficient mice demonstrated a lower level of αSMA positive cells as compared to controls, with decreased in MMP-9 and uPA expression
EMMPRIN promotes myofibroblasts differentiation and tissue contraction through the induction of alpha smooth muscle actin in vitro and in vivo. Myofibroblast’s effect on matrix remodeling may depend on the relative levels of TGFβ and EMMPRIN, tilting the balance towards synthesis or degradation respectively.
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