The secreted protein DEL-1 activates a β3 integrin-FAK-ERK1/2-RUNX2 pathway and promotes osteogenic differentiation and bone regeneration
© 2020 Yuh et al..
The integrin-binding secreted protein developmental endothelial locus-1 (DEL-1) is involved in the regulation of both the initiation and resolution of inflammation in different diseases, including periodontitis, an oral disorder characterized by inflammatory bone loss. Here, using a mouse model of bone regeneration and in vitro cell-based mechanistic studies, we investigated whether and how DEL-1 can promote alveolar bone regeneration during resolution of experimental periodontitis. Compared with WT mice, mice lacking DEL-1 or expressing a DEL-1 variant with an Asp-to-Glu substitution in the RGD motif ("RGE point mutant"), which does not interact with RGD-dependent integrins, exhibited defective bone regeneration. Local administration of DEL-1 or of its N-terminal segment containing the integrin-binding RGD motif, but not of the RGE point mutant, reversed the defective bone regeneration in the DEL-1-deficient mice. Moreover, DEL-1 (but not the RGE point mutant) promoted osteogenic differentiation of MC3T3-E1 osteoprogenitor cells or of primary calvarial osteoblastic cells in a β3 integrin-dependent manner. The ability of DEL-1 to promote in vitro osteogenesis, indicated by induction of osteogenic genes such as the master transcription factor Runt-related transcription factor-2 (Runx2) and by mineralized nodule formation, depended on its capacity to induce the phosphorylation of focal adhesion kinase (FAK) and of extracellular signal-regulated kinase 1/2 (ERK1/2). We conclude that DEL-1 can activate a β3 integrin-FAK-ERK1/2-RUNX2 pathway in osteoprogenitors and promote new bone formation in mice. These findings suggest that DEL-1 may be therapeutically exploited to restore bone lost due to periodontitis and perhaps other osteolytic conditions.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:295 |
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| Enthalten in: |
The Journal of biological chemistry - 295(2020), 21 vom: 22. Mai, Seite 7261-7273 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yuh, Da-Yo [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 23.12.2020 Date Revised 29.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1074/jbc.RA120.013024 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM308651588 |
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| 041 | |a eng | ||
| 100 | 1 | |a Yuh, Da-Yo |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The secreted protein DEL-1 activates a β3 integrin-FAK-ERK1/2-RUNX2 pathway and promotes osteogenic differentiation and bone regeneration |
| 264 | 1 | |c 2020 | |
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| 500 | |a Date Completed 23.12.2020 | ||
| 500 | |a Date Revised 29.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 Yuh et al. | ||
| 520 | |a The integrin-binding secreted protein developmental endothelial locus-1 (DEL-1) is involved in the regulation of both the initiation and resolution of inflammation in different diseases, including periodontitis, an oral disorder characterized by inflammatory bone loss. Here, using a mouse model of bone regeneration and in vitro cell-based mechanistic studies, we investigated whether and how DEL-1 can promote alveolar bone regeneration during resolution of experimental periodontitis. Compared with WT mice, mice lacking DEL-1 or expressing a DEL-1 variant with an Asp-to-Glu substitution in the RGD motif ("RGE point mutant"), which does not interact with RGD-dependent integrins, exhibited defective bone regeneration. Local administration of DEL-1 or of its N-terminal segment containing the integrin-binding RGD motif, but not of the RGE point mutant, reversed the defective bone regeneration in the DEL-1-deficient mice. Moreover, DEL-1 (but not the RGE point mutant) promoted osteogenic differentiation of MC3T3-E1 osteoprogenitor cells or of primary calvarial osteoblastic cells in a β3 integrin-dependent manner. The ability of DEL-1 to promote in vitro osteogenesis, indicated by induction of osteogenic genes such as the master transcription factor Runt-related transcription factor-2 (Runx2) and by mineralized nodule formation, depended on its capacity to induce the phosphorylation of focal adhesion kinase (FAK) and of extracellular signal-regulated kinase 1/2 (ERK1/2). We conclude that DEL-1 can activate a β3 integrin-FAK-ERK1/2-RUNX2 pathway in osteoprogenitors and promote new bone formation in mice. These findings suggest that DEL-1 may be therapeutically exploited to restore bone lost due to periodontitis and perhaps other osteolytic conditions | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a bone | |
| 650 | 4 | |a bone loss | |
| 650 | 4 | |a bone regeneration | |
| 650 | 4 | |a developmental endothelial locus-1 (DEL-1) | |
| 650 | 4 | |a extracellular matrix | |
| 650 | 4 | |a inflammation | |
| 650 | 4 | |a integrin | |
| 650 | 4 | |a osteoblast | |
| 650 | 4 | |a osteogenesis | |
| 650 | 4 | |a periodontal disease | |
| 650 | 4 | |a periodontitis | |
| 650 | 7 | |a Calcium-Binding Proteins |2 NLM | |
| 650 | 7 | |a Cell Adhesion Molecules |2 NLM | |
| 650 | 7 | |a Core Binding Factor Alpha 1 Subunit |2 NLM | |
| 650 | 7 | |a Edil3 protein, mouse |2 NLM | |
| 650 | 7 | |a Integrin beta3 |2 NLM | |
| 650 | 7 | |a Runx2 protein, mouse |2 NLM | |
| 650 | 7 | |a Focal Adhesion Kinase 1 |2 NLM | |
| 650 | 7 | |a EC 2.7.10.2 |2 NLM | |
| 650 | 7 | |a Ptk2 protein, mouse |2 NLM | |
| 650 | 7 | |a EC 2.7.10.2 |2 NLM | |
| 650 | 7 | |a Mapk1 protein, mouse |2 NLM | |
| 650 | 7 | |a EC 2.7.11.24 |2 NLM | |
| 650 | 7 | |a Mapk3 protein, mouse |2 NLM | |
| 650 | 7 | |a EC 2.7.11.24 |2 NLM | |
| 650 | 7 | |a Mitogen-Activated Protein Kinase 1 |2 NLM | |
| 650 | 7 | |a EC 2.7.11.24 |2 NLM | |
| 650 | 7 | |a Mitogen-Activated Protein Kinase 3 |2 NLM | |
| 650 | 7 | |a EC 2.7.11.24 |2 NLM | |
| 700 | 1 | |a Maekawa, Tomoki |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xiaofei |e verfasserin |4 aut | |
| 700 | 1 | |a Kajikawa, Tetsuhiro |e verfasserin |4 aut | |
| 700 | 1 | |a Bdeir, Khalil |e verfasserin |4 aut | |
| 700 | 1 | |a Chavakis, Triantafyllos |e verfasserin |4 aut | |
| 700 | 1 | |a Hajishengallis, George |e verfasserin |4 aut | |
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| 856 | 4 | 0 | |u http://dx.doi.org/10.1074/jbc.RA120.013024 |3 Volltext |
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