{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T07:07:37Z","timestamp":1791443257208,"version":"4.3.3"},"reference-count":72,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T00:00:00Z","timestamp":1698105600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT\u2010156341"],"award-info":[{"award-number":["PJT\u2010156341"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000245","name":"Michael Smith Foundation for Health Research","doi-asserted-by":"publisher","award":["17650"],"award-info":[{"award-number":["17650"]}],"id":[{"id":"10.13039\/501100000245","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Periodontal Research"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To gain insights into how proteases signal to connective tissues cells in the periodontium.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The connective tissue degradation observed in periodontitis is largely due to matrix metalloproteinase (MMP) release by gingival fibroblasts. Granzyme B (GzmB) is a serine protease whose role in periodontitis is undefined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Human gingival crevicular fluid (GCF) samples were obtained from sites with periodontal disease and healthy control sites. GzmB was quantified in the GCF ([GzmB]\n                      <jats:sub>GCF<\/jats:sub>\n                      ) by ELISA. Gingival fibroblasts (GF) were cultured in the presence or absence of recombinant GzmB. Culture supernatants were analyzed by ELISA to quantify GzmB\u2010induced release of interstitial collagenase (MMP\u20101). In some experiments, cells were pre\u2010treated with the inhibitor PD98059 to block MEK\/ERK signaling. The protease\u2010activated receptor\u20101 (PAR\u20101) was blocked with ATAP\u20102 neutralizing antibody prior to GzmB stimulation. Systemic MMP\u20101 levels were measured in plasma from wild\u2010type (\n                      <jats:italic>WT<\/jats:italic>\n                      ) and granzyme\u2010B\u2010knockout (\n                      <jats:italic>GzmB<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      ) mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The [GzmB]\n                      <jats:sub>GCF<\/jats:sub>\n                      in human samples was ~4\u20135 fold higher at sites of periodontal disease (gingivitis\/periodontitis) compared to healthy control sites, suggesting an association between GzmB and localized matrix degradation. GzmB induced a ~4\u20135\u2010fold increase in MMP\u20101 secretion by cultured fibroblasts. GzmB induced phosphorylation of Erk1\/2, which was abrogated by PD98059. GzmB\u2010induced upregulation of MMP\u20101 secretion was also reduced by PD98059. Blockade of PAR\u20101 function by ATAP\u20102 abrogated the increase in MMP\u20101 secretion by GF. Circulating MMP\u20101 was similar in\n                      <jats:italic>WT<\/jats:italic>\n                      and\n                      <jats:italic>GzmB<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice, suggesting that GzmB's effects on MMP\u20101 release are not reflected systemically.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These data point to a novel GzmB\u2010driven signaling pathway in fibroblasts in which MMP\u20101 secretion is upregulated in a PAR1\u2010 and Erk1\/2\u2010dependent manner.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/jre.13190","type":"journal-article","created":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T05:42:18Z","timestamp":1698126138000},"page":"94-103","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Granzyme B promotes matrix metalloproteinase\u20101 (\n                    <scp>MMP<\/scp>\n                    \u20101) release from gingival fibroblasts in a\n                    <scp>PAR1<\/scp>\n                    \u2010 and Erk1\/2\u2010dependent manner: A novel role in periodontal inflammation"],"prefix":"10.1111","volume":"59","author":[{"given":"Mohamed","family":"Ben\u2010Eltriki","sequence":"first","affiliation":[{"name":"Centre for Blood Research University of British Columbia  Vancouver British Columbia Canada"},{"name":"Department of Oral Biological and Medical Sciences University of British Columbia  Vancouver British Columbia 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