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Dorsomorphin attenuates Jagged1-induced mineralization in human dental pulp cells.

AIM
To investigate whether TGF-β/BMP signaling participates in Jagged1-induced osteogenic differentiation in human dental pulp cells (hDPs).


METHODOLOGY
Bioinformatic analysis of publicly available RNA sequencing data of Jagged1 treated hDPs was performed using NetworkAnalyst. The mRNA expression was validated using real-time polymerase chain reaction. hDPs were seeded on Jagged1 immobilized surface in the presence or absence of TGF-β or BMP inhibitor. Osteogenic differentiation was evaluated using alkaline phosphatase staining, osteogenic marker gene expression, and mineralization assay. Statistical analyses were performed using a Kruskal Wallis test, followed by a pairwise comparison for more than three group comparison. Mann Whitney U test was employed for two group comparison. The statistical significance was considered at p< 0.05.


RESULTS
Jagged1 treatment in growth medium significantly promoted TGFB1, TGFB2, and TGFB3 while significantly inhibited BMP2, BMP4, and BMP6 mRNA expression (p<0.05). In osteogenic induction medium, Jagged1 significantly upregulated TGFB1, TGFB2, and TGFB3 at day 1 and 3 (p<0.05). Pretreatment with TGF-β1, TGF-β2, or TGF-β3 prior to osteogenic induction resulted in the significant increase of osteogenic marker gene expression, collagen type 1 protein expression, alkaline phosphatase enzymatic activity, and mineral deposition (p<0.05). However, TGF-β signaling inhibition with SB431542 (4 μM) or SB505124 (47 and 129 nM) failed to attenuate the effect of Jagged1-induced osteogenic differentiation in hDPs. Dorsomorphin (4 and 8 μM) treatment significantly abolished the effect of Jagged1 on mineralization by hDPs (p<0.05).


CONCLUSION
Notch signaling activation by Jagged1 modulated TGF-β and BMP ligand expression. Dorsomorphin, but not TGF-β receptor inhibitor, attenuated Jagged1-induced osteogenic differentiation in hDPs.