MMP-13 regulates growth of wound granulation tissue and modulates gene expression signatures involved in inflammation, proteolysis, and cell viability
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(-/...
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| Veröffentlicht in: | PloS one 2012-08, Vol.7 (8), p.e42596 |
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| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0042596 |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0042596</identifier><identifier>PMID: 22880047</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>ADAM Proteins - genetics ; ADAM Proteins - metabolism ; ADAMTS4 Protein ; Angiogenesis ; Animals ; Apoptosis ; Biology ; Blood vessels ; Cell Differentiation - genetics ; Cell morphology ; Cell Survival - genetics ; Cellulose ; Collagen ; Collagen - metabolism ; Collagenase 3 ; Cytokines ; Cytology ; Dermatology ; Down-Regulation - genetics ; Fibroblasts ; Gelatinase A ; Gelatinase B ; Gels ; Gene expression ; Gene Expression Profiling ; Gene Regulatory Networks - genetics ; Genes ; Genomics ; Granulation ; Granulation Tissue - blood supply ; Granulation Tissue - pathology ; Growth ; Growth factors ; Hospitals ; Inflammation ; Inflammation - genetics ; Inflammation - pathology ; Inflammatory response ; Interleukin 6 ; Kinases ; Laboratories ; Leukocytes ; Male ; Matrix metalloproteinase ; Matrix Metalloproteinase 13 - genetics ; Matrix Metalloproteinase 13 - metabolism ; Matrix Metalloproteinase 2 - metabolism ; Matrix metalloproteinases ; Melanoma ; Mice ; Microvasculature ; Myofibroblasts - pathology ; Neovascularization, Pathologic - enzymology ; Neovascularization, Pathologic - genetics ; Neovascularization, Pathologic - pathology ; Neuropeptide Y ; Neuropeptide Y - genetics ; Neuropeptide Y - metabolism ; Platelet-derived growth factor ; Procollagen N-Endopeptidase - genetics ; Procollagen N-Endopeptidase - metabolism ; Proteases ; Proteolysis ; Rodents ; Skin ; Skin - pathology ; Stromelysin 1 ; Time Factors ; Tissues ; Wound care ; Wound healing ; Wound Healing - genetics</subject><ispartof>PloS one, 2012-08, Vol.7 (8), p.e42596</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>Toriseva et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2012 Toriseva et al 2012 Toriseva et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c743t-1b041f37b55b8164174e4fe2f461a42083cfc605857926a2dcd2d9e65bddbc0c3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413640/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413640/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22880047$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Yang, Chuen-Mao</contributor><creatorcontrib>Toriseva, Mervi</creatorcontrib><creatorcontrib>Laato, Matti</creatorcontrib><creatorcontrib>Carpén, Olli</creatorcontrib><creatorcontrib>Ruohonen, Suvi T</creatorcontrib><creatorcontrib>Savontaus, Eriika</creatorcontrib><creatorcontrib>Inada, Masaki</creatorcontrib><creatorcontrib>Krane, Stephen M</creatorcontrib><creatorcontrib>Kähäri, Veli-Matti</creatorcontrib><title>MMP-13 regulates growth of wound granulation tissue and modulates gene expression signatures involved in inflammation, proteolysis, and cell viability</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>ADAM Proteins - genetics</subject><subject>ADAM Proteins - metabolism</subject><subject>ADAMTS4 Protein</subject><subject>Angiogenesis</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biology</subject><subject>Blood vessels</subject><subject>Cell Differentiation - genetics</subject><subject>Cell morphology</subject><subject>Cell Survival - genetics</subject><subject>Cellulose</subject><subject>Collagen</subject><subject>Collagen - metabolism</subject><subject>Collagenase 3</subject><subject>Cytokines</subject><subject>Cytology</subject><subject>Dermatology</subject><subject>Down-Regulation - genetics</subject><subject>Fibroblasts</subject><subject>Gelatinase A</subject><subject>Gelatinase B</subject><subject>Gels</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Regulatory Networks - genetics</subject><subject>Genes</subject><subject>Genomics</subject><subject>Granulation</subject><subject>Granulation Tissue - blood supply</subject><subject>Granulation Tissue - pathology</subject><subject>Growth</subject><subject>Growth factors</subject><subject>Hospitals</subject><subject>Inflammation</subject><subject>Inflammation - genetics</subject><subject>Inflammation - pathology</subject><subject>Inflammatory response</subject><subject>Interleukin 6</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Leukocytes</subject><subject>Male</subject><subject>Matrix metalloproteinase</subject><subject>Matrix Metalloproteinase 13 - genetics</subject><subject>Matrix Metalloproteinase 13 - metabolism</subject><subject>Matrix Metalloproteinase 2 - metabolism</subject><subject>Matrix metalloproteinases</subject><subject>Melanoma</subject><subject>Mice</subject><subject>Microvasculature</subject><subject>Myofibroblasts - pathology</subject><subject>Neovascularization, Pathologic - enzymology</subject><subject>Neovascularization, Pathologic - genetics</subject><subject>Neovascularization, Pathologic - pathology</subject><subject>Neuropeptide Y</subject><subject>Neuropeptide Y - genetics</subject><subject>Neuropeptide Y - metabolism</subject><subject>Platelet-derived growth factor</subject><subject>Procollagen N-Endopeptidase - genetics</subject><subject>Procollagen N-Endopeptidase - metabolism</subject><subject>Proteases</subject><subject>Proteolysis</subject><subject>Rodents</subject><subject>Skin</subject><subject>Skin - pathology</subject><subject>Stromelysin 1</subject><subject>Time Factors</subject><subject>Tissues</subject><subject>Wound care</subject><subject>Wound healing</subject><subject>Wound Healing - genetics</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk91q2zAYhs3YWLtsdzA2w2Bs0GT6s-ycDErZT6ClY3-nQpZkR0G2UklOmxvZ9U5OnBKPHgwZJH163lfWJ31J8hKCGcQ5_LCynWu5ma1tq2YAEJTN6aPkFM4xmlIE8OOj8UnyzPsVABkuKH2anCBUFFGSnyZ_rq6-TSFOnao7w4Pyae3sbVimtkpvbdfKOOdtv6RtmwbtfadSHsONlQeBalWq7tZOed9DXtctD12cprrdWLNRMg7iVxneNDujs3TtbFDWbL32Zzs_oYxJN5qX2uiwfZ48qbjx6sXQT5Jfnz_9vPg6vbz-srg4v5yKnOAwhSUgsMJ5mWVlASmBOVGkUqgiFHKCQIFFJSjIiiyfI8qRFBLJuaJZKWUpgMCT5PXed22sZ0NKPYMY0YzgIiZskiz2hLR8xdZON9xtmeWa7QLW1Yy7oIVRrMJClLJEvCwloXnBqUCAFlJQzIuymkevj8NuXdkoKVQbHDcj0_FKq5esthuGCcSUgGjwbjBw9qZTPrBG-z5zvFW2i_8NMIZZnmMY0Tf_oA-fbqBqHg8Qr8jGfUVvys4jgkEGCI3U7AEqNqkaLeL7q3SMjwTvR4LIBHUXat55zxY_vv8_e_17zL49YpeKm7D01nT9m_JjkOxB4az3TlX3SYaA9eVzyAbry4cN5RNlr44v6F50qBf8F7wRGHA</recordid><startdate>20120807</startdate><enddate>20120807</enddate><creator>Toriseva, Mervi</creator><creator>Laato, Matti</creator><creator>Carpén, Olli</creator><creator>Ruohonen, Suvi T</creator><creator>Savontaus, Eriika</creator><creator>Inada, Masaki</creator><creator>Krane, Stephen M</creator><creator>Kähäri, Veli-Matti</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120807</creationdate><title>MMP-13 regulates growth of wound granulation tissue and modulates gene expression signatures involved in inflammation, proteolysis, and cell viability</title><author>Toriseva, Mervi ; Laato, Matti ; Carpén, Olli ; Ruohonen, Suvi T ; Savontaus, Eriika ; Inada, Masaki ; Krane, Stephen M ; Kähäri, Veli-Matti</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c743t-1b041f37b55b8164174e4fe2f461a42083cfc605857926a2dcd2d9e65bddbc0c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>ADAM Proteins - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Toriseva, Mervi</au><au>Laato, Matti</au><au>Carpén, Olli</au><au>Ruohonen, Suvi T</au><au>Savontaus, Eriika</au><au>Inada, Masaki</au><au>Krane, Stephen M</au><au>Kähäri, Veli-Matti</au><au>Yang, Chuen-Mao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MMP-13 regulates growth of wound granulation tissue and modulates gene expression signatures involved in inflammation, proteolysis, and cell viability</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-08-07</date><risdate>2012</risdate><volume>7</volume><issue>8</issue><spage>e42596</spage><pages>e42596-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22880047</pmid><doi>10.1371/journal.pone.0042596</doi><tpages>e42596</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-08, Vol.7 (8), p.e42596 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1326543805 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | ADAM Proteins - genetics ADAM Proteins - metabolism ADAMTS4 Protein Angiogenesis Animals Apoptosis Biology Blood vessels Cell Differentiation - genetics Cell morphology Cell Survival - genetics Cellulose Collagen Collagen - metabolism Collagenase 3 Cytokines Cytology Dermatology Down-Regulation - genetics Fibroblasts Gelatinase A Gelatinase B Gels Gene expression Gene Expression Profiling Gene Regulatory Networks - genetics Genes Genomics Granulation Granulation Tissue - blood supply Granulation Tissue - pathology Growth Growth factors Hospitals Inflammation Inflammation - genetics Inflammation - pathology Inflammatory response Interleukin 6 Kinases Laboratories Leukocytes Male Matrix metalloproteinase Matrix Metalloproteinase 13 - genetics Matrix Metalloproteinase 13 - metabolism Matrix Metalloproteinase 2 - metabolism Matrix metalloproteinases Melanoma Mice Microvasculature Myofibroblasts - pathology Neovascularization, Pathologic - enzymology Neovascularization, Pathologic - genetics Neovascularization, Pathologic - pathology Neuropeptide Y Neuropeptide Y - genetics Neuropeptide Y - metabolism Platelet-derived growth factor Procollagen N-Endopeptidase - genetics Procollagen N-Endopeptidase - metabolism Proteases Proteolysis Rodents Skin Skin - pathology Stromelysin 1 Time Factors Tissues Wound care Wound healing Wound Healing - genetics |
| title | MMP-13 regulates growth of wound granulation tissue and modulates gene expression signatures involved in inflammation, proteolysis, and cell viability |
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