Granzyme B promotes matrix metalloproteinase-1 (MMP-1) release from gingival fibroblasts in a PAR1- and Erk1/2-dependent manner : A novel role in periodontal inflammation
© 2023 The Authors. Journal of Periodontal Research published by John Wiley & Sons Ltd..
OBJECTIVE: To gain insights into how proteases signal to connective tissues cells in the periodontium.
BACKGROUND: 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.
METHODS: Human gingival crevicular fluid (GCF) samples were obtained from sites with periodontal disease and healthy control sites. GzmB was quantified in the GCF ([GzmB]GCF ) by ELISA. Gingival fibroblasts (GF) were cultured in the presence or absence of recombinant GzmB. Culture supernatants were analyzed by ELISA to quantify GzmB-induced release of interstitial collagenase (MMP-1). In some experiments, cells were pre-treated with the inhibitor PD98059 to block MEK/ERK signaling. The protease-activated receptor-1 (PAR-1) was blocked with ATAP-2 neutralizing antibody prior to GzmB stimulation. Systemic MMP-1 levels were measured in plasma from wild-type (WT) and granzyme-B-knockout (GzmB-/- ) mice.
RESULTS: The [GzmB]GCF in human samples was ~4-5 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 ~4-5-fold increase in MMP-1 secretion by cultured fibroblasts. GzmB induced phosphorylation of Erk1/2, which was abrogated by PD98059. GzmB-induced upregulation of MMP-1 secretion was also reduced by PD98059. Blockade of PAR-1 function by ATAP-2 abrogated the increase in MMP-1 secretion by GF. Circulating MMP-1 was similar in WT and GzmB-/- mice, suggesting that GzmB's effects on MMP-1 release are not reflected systemically.
CONCLUSION: These data point to a novel GzmB-driven signaling pathway in fibroblasts in which MMP-1 secretion is upregulated in a PAR1- and Erk1/2-dependent manner.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:59 |
|---|---|
| Enthalten in: |
Journal of periodontal research - 59(2024), 1 vom: 15. Feb., Seite 94-103 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Ben-Eltriki, Mohamed [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 14.02.2024 Date Revised 14.02.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1111/jre.13190 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM363659803 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM363659803 | ||
| 003 | DE-627 | ||
| 005 | 20240214232852.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1111/jre.13190 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1292.xml |
| 035 | |a (DE-627)NLM363659803 | ||
| 035 | |a (NLM)37873693 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Ben-Eltriki, Mohamed |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Granzyme B promotes matrix metalloproteinase-1 (MMP-1) release from gingival fibroblasts in a PAR1- and Erk1/2-dependent manner |b A novel role in periodontal inflammation |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 14.02.2024 | ||
| 500 | |a Date Revised 14.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. Journal of Periodontal Research published by John Wiley & Sons Ltd. | ||
| 520 | |a OBJECTIVE: To gain insights into how proteases signal to connective tissues cells in the periodontium | ||
| 520 | |a BACKGROUND: 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 | ||
| 520 | |a METHODS: Human gingival crevicular fluid (GCF) samples were obtained from sites with periodontal disease and healthy control sites. GzmB was quantified in the GCF ([GzmB]GCF ) by ELISA. Gingival fibroblasts (GF) were cultured in the presence or absence of recombinant GzmB. Culture supernatants were analyzed by ELISA to quantify GzmB-induced release of interstitial collagenase (MMP-1). In some experiments, cells were pre-treated with the inhibitor PD98059 to block MEK/ERK signaling. The protease-activated receptor-1 (PAR-1) was blocked with ATAP-2 neutralizing antibody prior to GzmB stimulation. Systemic MMP-1 levels were measured in plasma from wild-type (WT) and granzyme-B-knockout (GzmB-/- ) mice | ||
| 520 | |a RESULTS: The [GzmB]GCF in human samples was ~4-5 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 ~4-5-fold increase in MMP-1 secretion by cultured fibroblasts. GzmB induced phosphorylation of Erk1/2, which was abrogated by PD98059. GzmB-induced upregulation of MMP-1 secretion was also reduced by PD98059. Blockade of PAR-1 function by ATAP-2 abrogated the increase in MMP-1 secretion by GF. Circulating MMP-1 was similar in WT and GzmB-/- mice, suggesting that GzmB's effects on MMP-1 release are not reflected systemically | ||
| 520 | |a CONCLUSION: These data point to a novel GzmB-driven signaling pathway in fibroblasts in which MMP-1 secretion is upregulated in a PAR1- and Erk1/2-dependent manner | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Granzyme B | |
| 650 | 4 | |a MAP kinases | |
| 650 | 4 | |a MMP-1 | |
| 650 | 4 | |a gingival crevicular fluid | |
| 650 | 4 | |a periodontitis | |
| 650 | 7 | |a Matrix Metalloproteinase 1 |2 NLM | |
| 650 | 7 | |a EC 3.4.24.7 |2 NLM | |
| 650 | 7 | |a Granzymes |2 NLM | |
| 650 | 7 | |a EC 3.4.21.- |2 NLM | |
| 650 | 7 | |a Receptor, PAR-1 |2 NLM | |
| 650 | 7 | |a Matrix Metalloproteinase 8 |2 NLM | |
| 650 | 7 | |a EC 3.4.24.34 |2 NLM | |
| 650 | 7 | |a Matrix Metalloproteinase 13 |2 NLM | |
| 650 | 7 | |a EC 3.4.24.- |2 NLM | |
| 650 | 7 | |a Matrix Metalloproteinase 3 |2 NLM | |
| 650 | 7 | |a EC 3.4.24.17 |2 NLM | |
| 700 | 1 | |a Ahmadi, Amir Reza |e verfasserin |4 aut | |
| 700 | 1 | |a Nakao, Yuya |e verfasserin |4 aut | |
| 700 | 1 | |a Golla, Kalyan |e verfasserin |4 aut | |
| 700 | 1 | |a Lakschevitz, Flavia |e verfasserin |4 aut | |
| 700 | 1 | |a Häkkinen, Lari |e verfasserin |4 aut | |
| 700 | 1 | |a Granville, David J |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Hugh |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of periodontal research |d 1966 |g 59(2024), 1 vom: 15. Feb., Seite 94-103 |w (DE-627)NLM000130044 |x 1600-0765 |7 nnns |
| 773 | 1 | 8 | |g volume:59 |g year:2024 |g number:1 |g day:15 |g month:02 |g pages:94-103 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1111/jre.13190 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 59 |j 2024 |e 1 |b 15 |c 02 |h 94-103 | ||