MMP-13 Regulates Growth of Wound Granulation Tissue and Modulates Gene Expression Signatures Involved in Inflammation, Proteolysis, and Cell Viability

<div><p>Proteinases play a pivotal role in wound healing by regulating cell-matrix interactions and availability of bioactive molecules. The role of matrix metalloproteinase-13 (MMP-13) in granulation tissue growth was studied in subcutaneously implanted viscose cellulose sponge in MMP-13 knockout (<em>Mmp13</em>^−/−) and wild type (WT) mice. The tissue samples were harvested at time points day 7, 14 and 21 and subjected to histological analysis and gene expression profiling. Granulation tissue growth was significantly reduced (42%) at day 21 in <em>Mmp13</em>^−/− mice. Granulation tissue in <em>Mmp13</em>^−/− mice showed delayed organization of myofibroblasts, increased microvascular density at day 14, and virtual absence of large vessels at day 21. Gene expression profiling identified differentially expressed genes in <em>Mmp13</em>^−/− mouse granulation tissue involved in biological functions including <em>inflammatory response</em>, <em>angiogenesis</em>, <em>cellular movement</em>, <em>cellular growth and proliferation</em> and <em>proteolysis</em>. Among genes linked to angiogenesis, <em>Adamts4</em> and <em>Npy</em> were significantly upregulated in early granulation tissue in <em>Mmp13^−/−</em> mice, and a set of genes involved in <em>leukocyte motility</em> including <em>Il6</em> were systematically downregulated at day 14. The expression of <em>Pdgfd</em> was downregulated in <em>Mmp13</em>^−/− granulation tissue in all time points. The expression of matrix metalloproteinases <em>Mmp2, Mmp3, Mmp9</em> was also significantly downregulated in granulation tissue of <em>Mmp13</em>^−/− mice compared to WT mice. <em>Mmp13</em>^−/− mouse skin fibroblasts displayed altered cell morphology and impaired ability to contract collagen gel and decreased production of MMP-2. These results provide evidence for an important role for MMP-13 in wound healing by coordinating cellular activities important in the growth and maturation of granulation tissue, including myofibroblast function, inflammation, angiogenesis, and proteolysis.</p>