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P. Qiu, G. Sosne; Thymosin Beta 4 (Tß4) Stimulates Matrix Metalloproteinase (MMP)–1 Expression in Human Cornea Epithelial Cells and Promotes MMP–Dependent Cell Migration in vitro After Scrape Wounding . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5027.
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The purpose of this study was to investigate the ability of Tß4 to induce MMP–1 expression and to test whether Tß4–mediated corneal epithelial cell migration is MMP–dependent.
RT–PCR and ELISA immunoassays were used to determine MMP–1 mRNA production and protein secretion in response to Tß4 (1 µg/ml) treatment in both primary (HCEC) and immortalized human cornea epithelial cells (HCET). We also studied the effects of transient over–expression of c–Jun (wild–type and dominant negative) on epithelial cell MMP–1 expression. Further, we measured Tß4–mediated HCET migration after scrape wounding in the absence and presence of both general and specific MMP inhibitors.
After 3 hours of treatment, Tß4 induced MMP–1 mRNA transcription in HCET and the increased levels continued until 24 hours after treatment. Similarly, Tß4 treatment increased MMP–1 mRNA and protein levels in HCEC in a dose–dependent manner. Enforced HCET expression of c–JUN, a critical transcription factor for MMP expression, was sufficient to stimulate MMP–1 expression, while its dominant negative suppressed MMP–1 production. Further, Tß4 promoted HCET migration after scrape wounding of monolayer cultures. The general MMP inhibitor GM6001, but not its negative control, blocked Tß4–promoted HCET migration. In addition, XG076, an inhibitor of pro–MMP activation, as well as the specific MMP–1 inhibitor, MMP inhibitor I, repressed Tß4–promoted HCET migration after scrape wounding.
These novel findings show that Tß4 stimulates MMP–1 production in human cornea epithelial cells and its ability to promote cell migration after wounding is dependent upon MMP activation. We suggest that Tß4 targets c–JUN transcription regulatory networks to stimulate corneal epithelial cell MMP production and, in turn, to promote epithelial cell migration during corneal wound healing.
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