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Published on: January 17, 2012
MMP-13 regulates growth of wound granulation tissue and modulates gene expression signatures involved in
Mervi Toriseva1, Matti Laato, Olli Carpén
1Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland.
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.
Insights
Matrix metalloproteinase-13 (MMP-13) is crucial for wound healing, coordinating granulation tissue growth, myofibroblast organization, and angiogenesis. Its absence impairs these processes, highlighting MMP-13
Area of Science:
- Biochemistry
- Cell Biology
- Wound Healing Research
Background:
- Proteinases, particularly matrix metalloproteinases (MMPs), are vital for wound healing.
- Matrix metalloproteinase-13 (MMP-13) is implicated in regulating extracellular matrix remodeling and cell behavior during tissue repair.
Purpose of the Study:
- To investigate the specific role of MMP-13 in granulation tissue formation and maturation.
- To elucidate the impact of MMP-13 deficiency on cellular and molecular events during wound healing.
Main Methods:
- Utilized a murine model with MMP-13 knockout (Mmp13(-/-)) and wild-type (WT) mice.
- Implanted viscose cellulose sponges subcutaneously to induce granulation tissue formation.
- Conducted histological analysis and gene expression profiling at days 7, 14, and 21.
- Performed in vitro assays on Mmp13(-/-) mouse skin fibroblasts.
Main Results:
- MMP-13 deficiency significantly reduced granulation tissue growth by 42% at day 21.
- Mmp13(-/-) mice exhibited delayed myofibroblast organization, altered vascularization, and changes in inflammatory and angiogenic gene expression.
- MMP-13 knockout fibroblasts showed impaired collagen gel contraction and reduced MMP-2 production.
Conclusions:
- MMP-13 plays a critical role in coordinating cellular activities essential for granulation tissue growth and maturation.
- MMP-13 influences myofibroblast function, inflammation, angiogenesis, and proteolysis during wound healing.
- These findings underscore MMP-13's importance as a therapeutic target for enhancing wound repair.
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