DLK1 and DLK2, two non-canonical ligands of NOTCH receptors, differentially modulate the osteogenic differentiation of mesenchymal C3H10T1/2 cells.
Cell Differentiation
/ physiology
Osteogenesis
/ physiology
Animals
Intercellular Signaling Peptides and Proteins
/ metabolism
Calcium-Binding Proteins
/ metabolism
Mice
Receptors, Notch
/ metabolism
Mesenchymal Stem Cells
/ metabolism
Signal Transduction
/ physiology
Cell Line
Osteoblasts
/ metabolism
DLK
ERK1/2 MAPK
Mesenchymal C3H10T1/2 cells
NOTCH
Osteogenesis
p38 MAPK
Journal
Biological research
ISSN: 0717-6287
Titre abrégé: Biol Res
Pays: England
ID NLM: 9308271
Informations de publication
Date de publication:
30 Oct 2024
30 Oct 2024
Historique:
received:
27
08
2024
accepted:
25
10
2024
medline:
30
10
2024
pubmed:
30
10
2024
entrez:
30
10
2024
Statut:
epublish
Résumé
C3H10T1/2 is a mesenchymal cell line capable of differentiating into osteoblasts, adipocytes and chondrocytes. The differentiation of these cells into osteoblasts is modulated by various transcription factors, such as RUNX2. Additionally, several interconnected signaling pathways, including the NOTCH pathway, play a crucial role in modulating their differentiation into mature bone cells. We have investigated the roles of DLK1 and DLK2, two non-canonical inhibitory ligands of NOTCH receptors, in the osteogenic differentiation of C3H10T1/2 cells. Our results corroborate existing evidence that DLK1 acts as an inhibitor of osteogenesis. In contrast, we demonstrate for the first time that DLK2 enhances this differentiation process. Additionally, our data suggest that NOTCH2, 3 and 4 receptors may promote osteogenesis, as indicated by their increased expression during this process, whereas NOTCH1 expression, which decreases during cell differentiation, might inhibit osteogenesis. Moreover, treatment with DAPT, a NOTCH signaling inhibitor, impeded osteogenic differentiation. We have confirmed the increase in ERK1/2 MAPK and p38 MAPK phosphorylation in C3H10T1/2 cells induced to differentiate to osteoblasts. Our new findings reveal increased ERK1/2 MAPK phosphorylation in differentiated C3H10T1/2 cells with a decrease in DLK1 expression or an overexpression of DLK2, which is coincident with the behavior of those transfectants where we have detected an increase in osteogenic differentiation. Additionally, p38 MAPK phosphorylation increases in differentiated C3H10T1/2 cells with reduced DLK1 levels. Our results suggest that DLK1 may inhibit osteogenesis, while DLK2 may promote it, by modulating NOTCH signaling and the phosphorylation of ERK1/2 and p38 MAPK pathways. Given the established inhibitory effect of DLK proteins on NOTCH signaling, these new insights could pave the way for developing future therapeutic strategies aimed at treating bone diseases.
Sections du résumé
BACKGROUND
BACKGROUND
C3H10T1/2 is a mesenchymal cell line capable of differentiating into osteoblasts, adipocytes and chondrocytes. The differentiation of these cells into osteoblasts is modulated by various transcription factors, such as RUNX2. Additionally, several interconnected signaling pathways, including the NOTCH pathway, play a crucial role in modulating their differentiation into mature bone cells. We have investigated the roles of DLK1 and DLK2, two non-canonical inhibitory ligands of NOTCH receptors, in the osteogenic differentiation of C3H10T1/2 cells.
RESULTS
RESULTS
Our results corroborate existing evidence that DLK1 acts as an inhibitor of osteogenesis. In contrast, we demonstrate for the first time that DLK2 enhances this differentiation process. Additionally, our data suggest that NOTCH2, 3 and 4 receptors may promote osteogenesis, as indicated by their increased expression during this process, whereas NOTCH1 expression, which decreases during cell differentiation, might inhibit osteogenesis. Moreover, treatment with DAPT, a NOTCH signaling inhibitor, impeded osteogenic differentiation. We have confirmed the increase in ERK1/2 MAPK and p38 MAPK phosphorylation in C3H10T1/2 cells induced to differentiate to osteoblasts. Our new findings reveal increased ERK1/2 MAPK phosphorylation in differentiated C3H10T1/2 cells with a decrease in DLK1 expression or an overexpression of DLK2, which is coincident with the behavior of those transfectants where we have detected an increase in osteogenic differentiation. Additionally, p38 MAPK phosphorylation increases in differentiated C3H10T1/2 cells with reduced DLK1 levels.
CONCLUSIONS
CONCLUSIONS
Our results suggest that DLK1 may inhibit osteogenesis, while DLK2 may promote it, by modulating NOTCH signaling and the phosphorylation of ERK1/2 and p38 MAPK pathways. Given the established inhibitory effect of DLK proteins on NOTCH signaling, these new insights could pave the way for developing future therapeutic strategies aimed at treating bone diseases.
Identifiants
pubmed: 39473022
doi: 10.1186/s40659-024-00561-7
pii: 10.1186/s40659-024-00561-7
doi:
Substances chimiques
Intercellular Signaling Peptides and Proteins
0
Calcium-Binding Proteins
0
Receptors, Notch
0
Dlk1 protein, mouse
0
Dlk2 protein, mouse
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
77Subventions
Organisme : The Health Council of the Regional Government of Castilla-La Mancha (Spain), supported by the Fondo Europeo de Desarrollo Regional (FEDER).
ID : ISBPLY/17/180501/000316
Informations de copyright
© 2024. The Author(s).
Références
Curr Biol. 2002 Mar 19;12(6):R200-2
pubmed: 11909545
Scientifica (Cairo). 2013;2013:684736
pubmed: 24416618
Bone. 2018 May;110:312-320
pubmed: 29499415
Cell Biol Int. 2014 Jun;38(6):729-36
pubmed: 24677709
Endocrinology. 2003 Dec;144(12):5631-9
pubmed: 12960086
Med Sci Monit Basic Res. 2016 Sep 26;22:95-106
pubmed: 27667570
FASEB J. 2017 Aug;31(8):3484-3496
pubmed: 28461338
J Cell Biochem. 2008 Jul 1;104(4):1342-55
pubmed: 18286543
Mol Med Rep. 2017 Oct;16(4):4127-4132
pubmed: 28765932
Front Biosci. 2001 Nov 01;6:A25-32
pubmed: 11689349
Nat Commun. 2019 Nov 6;10(1):5033
pubmed: 31695034
Exp Cell Res. 2005 Feb 15;303(2):343-59
pubmed: 15652348
Methods Mol Biol. 2022;2472:67-82
pubmed: 35674893
Arterioscler Thromb Vasc Biol. 2009 Jul;29(7):1104-11
pubmed: 19407244
Int J Biochem Cell Biol. 2019 Nov;116:105614
pubmed: 31550547
Biochem Biophys Res Commun. 2010 Feb 12;392(3):442-7
pubmed: 20079713
Biochem Biophys Res Commun. 2008 Feb 29;367(1):97-102
pubmed: 18162173
J Bone Miner Res. 2002 Feb;17(2):231-9
pubmed: 11811553
J Bone Miner Res. 2011 Oct;26(10):2548-51
pubmed: 21681814
Cell Tissue Res. 2020 Jan;379(1):169-179
pubmed: 31781870
Hormones (Athens). 2014 Jan-Mar;13(1):24-37
pubmed: 24722125
J Oral Sci. 2017;59(3):405-413
pubmed: 28904317
J Cell Biochem. 2011 Dec;112(12):3491-501
pubmed: 21793042
Cell. 2006 Mar 10;124(5):883-5
pubmed: 16530033
J Bone Miner Res. 2011 Jul;26(7):1457-71
pubmed: 21308776
Mol Cell. 2000 Feb;5(2):207-16
pubmed: 10882063
Biochim Biophys Acta. 2011 Jun;1813(6):1153-64
pubmed: 21419176
J Mol Biol. 2007 Apr 13;367(5):1281-93
pubmed: 17320900
Nucleic Acids Res. 1991 Jul 25;19(14):3998
pubmed: 1861990
J Cell Physiol. 2016 Dec;231(12):2652-63
pubmed: 26946465
J Biol Chem. 2004 Sep 3;279(36):37704-15
pubmed: 15178686
Cell Signal. 2016 Apr;28(4):246-54
pubmed: 26791579
Oncotarget. 2017 Jul 15;8(33):55405-55421
pubmed: 28903429
Sci Rep. 2017 Aug 1;7(1):7002
pubmed: 28765584
Int J Nanomedicine. 2020 Jun 30;15:4659-4676
pubmed: 32636624
Exp Cell Res. 2002 Apr 1;274(2):178-88
pubmed: 11900478
Curr Top Dev Biol. 2010;92:73-129
pubmed: 20816393
Int J Biol Macromol. 2017 Apr;97:460-467
pubmed: 28099888
J Bone Miner Res. 2004 May;19(5):841-52
pubmed: 15068508
Mol Endocrinol. 2009 Nov;23(11):1717-25
pubmed: 19541743
J Cell Physiol. 2018 Sep;233(9):6574-6582
pubmed: 29057471
Mol Cell Biol. 2004 Apr;24(8):3505-13
pubmed: 15060169
Aging (Albany NY). 2019 Dec 11;11(24):12476-12496
pubmed: 31825894
Int J Mol Sci. 2022 Jan 29;23(3):
pubmed: 35163478
PLoS One. 2015 Feb 18;10(2):e0118168
pubmed: 25692676
J Cell Biochem. 2018 Nov;119(11):9462-9473
pubmed: 30010216
Cell Death Dis. 2023 Sep 5;14(9):589
pubmed: 37669921
J Biol Chem. 2007 Mar 9;282(10):7339-51
pubmed: 17182623
J Mol Biol. 2007 Apr 13;367(5):1270-80
pubmed: 17320102
Mol Biol Rep. 2023 Apr;50(4):3217-3228
pubmed: 36705791