Abstract
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 (Mmp13 −/−) 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 Mmp13 −/− mice. Granulation tissue in Mmp13 −/− 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 Mmp13 −/− mouse granulation tissue involved in biological functions including inflammatory response, angiogenesis, cellular movement, cellular growth and proliferation and proteolysis. Among genes linked to angiogenesis, Adamts4 and Npy were significantly upregulated in early granulation tissue in Mmp13−/− mice, and a set of genes involved in leukocyte motility including Il6 were systematically downregulated at day 14. The expression of Pdgfd was downregulated in Mmp13 −/− granulation tissue in all time points. The expression of matrix metalloproteinases Mmp2, Mmp3, Mmp9 was also significantly downregulated in granulation tissue of Mmp13 −/− mice compared to WT mice. Mmp13 −/− 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.
Highlights
Wound repair is a fundamental process for survival of multicellular organisms
Delayed granulation tissue growth in Mmp132/2 mice To elucidate the role of matrix metalloproteinase-13 (MMP-13) in the formation of wound granulation tissue involved in the wound healing process, subcutaneously implanted viscose cellulose sponge (VCS) was used to induce granulation tissue growth
At 21 d, the Mmp132/2 granulation tissue was clearly different from wild type (WT) tissue as demonstrated by a significant reduction (42%, P,0.05) in the growth of granulation tissue in Mmp132/2 mice compared to WT mice at 21 d (Figure 1A and B)
Summary
Mammalian wound healing consists of functionally distinct and temporally overlapping processes, i.e. hemostasis and inflammation, re-epithelialization and granulation tissue formation, and tissue remodeling [1]. These processes involve functions of multiple cell types in distinct tissue compartments, and they are strictly orchestrated by various growth factors, cytokines and extracellular matrix (ECM) components [1,2]. MMPs are a family of Zn-dependent endopeptidases, which as a group can cleave a multitude of ECM proteins and non-matrix proteins, including other proteinases, proteinase inhibitors, growth factors, cytokines, and cell surface receptors [3,4]. Members of ADAM (a disintegrin and metalloproteinase domain) and ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin motifs) families, including ADAM-9 and ADAMTS-1, have been implicated in wound healing [5,6]
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