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E. A. Szliter, S. A. McClellan, R. P. Barrett, L. D. Hazlett; Testican-1/SPOCK1 Promotes Resistance Against P. aeruginosa-Induced Keratitis via Modulation of MMP-Driven Wound Healing and ECM Restoration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1199.
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Testican-1/SPOCK1 is a highly conserved chimeric proteoglycan encoded by the SPOCK1 gene. Protease regulatory activity has recently been demonstrated by this molecule and its family members, testican-2 and testican-3. This study tested the hypothesis that testican-1/SPOCK1 regulates corneal matrix metalloproteinase (MMP) expression and extracellular matrix (ECM) degradation, thus ameliorating disease outcome and promoting resistance against Pseudomonas (P.) aeruginosa-induced keratitis.
C57BL/6 (B6) and BALB/c mice were routinely infected with P. aeruginosa, and evaluated at various times post-infection (p.i.) for corneal expression of testican-1/SPOCK1 and MMP-2, -8, -11 and -13 by PCR array, real-time RT-PCR, ELISA, activity assays, zymography and immunohistochemistry. Next, B6 mice were treated with recombinant (r) human testican-1/SPOCK1, while expression of the proteoglycan was knocked down in BALB/c mice by siSPOCK1 treatment. Control mice were similarly treated with PBS/BSA and scrambled peptide, respectively. Animals were infected with P. aeruginosa and examined through 5 days p.i. by clinical score, slit-lamp photography and real-time RT-PCR for testican-1/SPOCK1 and MMP-2, -8, -11 and -13 expression.
BALB/c versus B6 mice expressed significantly higher mRNA and protein levels of testican-1/SPOCK1 after P. aeruginosa-induced ocular infection. MMP expression and activation also were disparate between the two mouse strains. After rSPOCK1 treatment in B6 mice, the overall disease response was significantly improved; in contrast, siRNA treatment of BALB/c mice converted the normally resistant response to susceptible.
These data support the role for testican-1/SPOCK1 in regulation of MMP expression and subsequent disease pathogenesis after P. aeruginosa-induced infection. Furthermore, they suggest a molecule that could be targeted for disease manipulation/treatment ultimately resulting in less stromal destruction and better disease outcome.
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