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Cited by 68Wnt/β-catenin signaling in development and cancerEndodontics and Root Canal Treatmentsdental development and anomalies

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Bone morphogenetic protein 2-induced human dental pulp cell differentiation involves p38 mitogen-activated protein kinase-activated canonical WNT pathway

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Yang, Jing, Ye, Ling, Hui, Tian-Qian, Yang, Dong-Mei, Huang, Ding-Ming, Zhou, Xue-Dong, Mao, Jeremy J, Wang, Cheng-Lin·2015·International Journal of Oral Science
DOI 10.1038/ijos.2015.7PMC PMC4817555
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Abstract

Both bone morphogenetic protein 2 (BMP2) and the wingless-type MMTV integration site (WNT)/β-catenin signalling pathway play important roles in odontoblast differentiation and dentinogenesis. Cross-talk between BMP2 and WNT/β-catenin in osteoblast differentiation and bone formation has been identified. However, the roles and mechanisms of the canonical WNT pathway in the regulation of BMP2 in dental pulp injury and repair remain largely unknown. Here, we demonstrate that BMP2 promotes the differentiation of human dental pulp cells (HDPCs) by activating WNT/β-catenin signalling, which is further mediated by p38 mitogen-activated protein kinase (MAPK) in vitro. BMP2 stimulation upregulated the expression of β-catenin in HDPCs, which was abolished by SB203580 but not by Noggin or LDN193189. Furthermore, BMP2 enhanced cell differentiation, which was not fully inhibited by Noggin or LDN193189. Instead, SB203580 partially blocked BMP2-induced β-catenin expression and cell differentiation. Taken together, these data suggest a possible mechanism by which the elevation of β-catenin resulting from BMP2 stimulation is mediated by the p38 MAPK pathway, which sheds light on the molecular mechanisms of BMP2-mediated pulp reparative dentin formation. Researchers have clarified the molecular interactions that underpin the formation and regeneration of dentin in human teeth. Dentin is the layer of calcified tissue directly beneath the surface enamel of a tooth. It is formed and sustained by the differentiation of cells in the tooth pulp that lies beneath the dentin layer. Chenglin Wang and co-workers at Sichuan University in China, with colleagues at Columbia University, New York, USA, studied human dental pulp cells in vitro. They demonstrated that bone morphogenetic protein 2 (BMP2) promotes the differentiation of pulp cells to form dentin by affecting signaling pathways known to be involved. Identifying the links between the growth factor BMP2, and β-catenin and p38, proteins in these pathways, will improve understanding of dentin formation and repair after injury.

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Figure 1 BMP2 stimulation activates the WNT/β-catenin signalling pathway and promotes differentiation partly via the canonical WNT pathway in HDPCs. (a, b) HDPCs were starved for 2 h and then stimulated with 30 ng·mL −1 rhBMP2 for the indicated times. BMP2 significantly upregulates the expression of β-catenin in the cytoplasm, nucleolus and whole-cell lysates of HDPCs. GAPDH and Histone3 were used as normalization controls. (c) After stimulation with 30 ng·mL−1 rhBMP2 for 6 h, immunofluorescence staining for β-catenin (red) showed that BMP2 promotes nuclear translocation of β-catenin in HDPCs. GAPDH was used as the normalization control. Bar=50 μm. (d) BMP2 significantly upregulates the expression of Lef1 mRNA at 24 h. (e) Luciferase activity is upregulated by treatment with 30 ng·mL−1 rhBMP2 for 24 h after co-transfection of HDPCs with the TOPflash and PGL4-TK plasmids using Neon Transfection Systems. (f, g) HDPCs were cultured in osteogenic medium with or without 20 ng·mL−1 rhBMP2 for 4 days or 10 days, after which ALPase and Alizarin red S staining was performed. Following rhDKK1 or XAV939 treatment, BMP2 still promotes TOPflash luciferase activity and cell differentiation. Bar = 100 μm in f; Bar = 200 μm in g. *Significant differences (P < .05) versus the control. ALPase, alkaline phosphatase; BMP, bone morphogenetic protein; DAPI, diamidino-phenyl-indole; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HDPC, human dental pulp cell; Lef, lymphoid enhancer-binding factor; qPCR, quantitative polymerase chain reaction.
Figure 1 BMP2 stimulation activates the WNT/β-catenin signalling pathway and promotes differentiation partly via the canonical WNT pathway in HDPCs. (a, b) HDPCs were starved for 2 h and then stimulated with 30 ng·mL −1 rhBMP2 for the indicated times. BMP2 significantly upregulates the expression of β-catenin in the cytoplasm, nucleolus and whole-cell lysates of HDPCs. GAPDH and Histone3 were used as normalization controls. (c) After stimulation with 30 ng·mL−1 rhBMP2 for 6 h, immunofluorescence staining for β-catenin (red) showed that BMP2 promotes nuclear translocation of β-catenin in HDPCs. GAPDH was used as the normalization control. Bar=50 μm. (d) BMP2 significantly upregulates the expression of Lef1 mRNA at 24 h. (e) Luciferase activity is upregulated by treatment with 30 ng·mL−1 rhBMP2 for 24 h after co-transfection of HDPCs with the TOPflash and PGL4-TK plasmids using Neon Transfection Systems. (f, g) HDPCs were cultured in osteogenic medium with or without 20 ng·mL−1 rhBMP2 for 4 days or 10 days, after which ALPase and Alizarin red S staining was performed. Following rhDKK1 or XAV939 treatment, BMP2 still promotes TOPflash luciferase activity and cell differentiation. Bar = 100 μm in f; Bar = 200 μm in g. *Significant differences (P < .05) versus the control. ALPase, alkaline phosphatase; BMP, bone morphogenetic protein; DAPI, diamidino-phenyl-indole; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HDPC, human dental pulp cell; Lef, lymphoid enhancer-binding factor; qPCR, quantitative polymerase chain reaction.CC BY-NC-SA · PubMed Central
Figure 2 BMP2 activates canonical BMP and non-canonical p38 MAPK signalling. (a) Starvation for 2 h and treatment with 30 ng·mL−1 rhBMP2 upregulates the expression of p-smad1/5/8 in HDPCs, as determined via western blot analysis. (b) rhNoggin (500 ng·mL−1) pretreatment for 12 h or LDN193189 (1 µmol·L−1) pretreatment for 1 h, followed by 30 ng·mL−1 BMP2 stimulation, promotes the expression of β-catenin in whole-cell lysates. (c) As shown in a, BMP2 upregulates the expression of p-p38 in HDPCs. (d) Starvation for 2 h and pretreatment with 1 µmol·L−1 LDN193189 or 30 µmol·L−1 SB203580 for 1 h before 30 ng·mL−1 rhBMP2 stimulation. Both LDN and SB treatment can downregulate the BMP2-induced expression of p-p38. ALPase, alkaline phosphatase; BMP, bone morphogenetic protein; DAPI, diamidino-phenyl-indole; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HDPC, human dental pulp cell; p-Smad1/5/8, phosphor-Smad1/5/8; p-p38, phosphor-p38.
Figure 2 BMP2 activates canonical BMP and non-canonical p38 MAPK signalling. (a) Starvation for 2 h and treatment with 30 ng·mL−1 rhBMP2 upregulates the expression of p-smad1/5/8 in HDPCs, as determined via western blot analysis. (b) rhNoggin (500 ng·mL−1) pretreatment for 12 h or LDN193189 (1 µmol·L−1) pretreatment for 1 h, followed by 30 ng·mL−1 BMP2 stimulation, promotes the expression of β-catenin in whole-cell lysates. (c) As shown in a, BMP2 upregulates the expression of p-p38 in HDPCs. (d) Starvation for 2 h and pretreatment with 1 µmol·L−1 LDN193189 or 30 µmol·L−1 SB203580 for 1 h before 30 ng·mL−1 rhBMP2 stimulation. Both LDN and SB treatment can downregulate the BMP2-induced expression of p-p38. ALPase, alkaline phosphatase; BMP, bone morphogenetic protein; DAPI, diamidino-phenyl-indole; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HDPC, human dental pulp cell; p-Smad1/5/8, phosphor-Smad1/5/8; p-p38, phosphor-p38.CC BY-NC-SA · PubMed Central
Figure 3 Blockade of the p38 signalling pathway can reduce the BMP2-induced activation of WNT/β-catenin signalling and cell differentiation. (a) After starvation for 2 h, pretreatment with 30 µmol·L−1 SB203580 for 2 h, and then stimulation of HDPCs with 30 ng·mL−1 rhBMP2 for various time periods; SB203580 treatment blocks the activation of β-catenin by BMP2. (b) After 6 h, immunofluorescence staining showed that SB203580 treatment reduces the translocation of β-catenin by BMP. Bar = 50 μm. (c) After 24 h, qPCR showed that SB203580 treatment reduces the expression of lef1 mRNA. (d) Treatment with Noggin, LDN or SB partially blocks BMP2-induced HDPC differentiation, whereas combined treatment with LDN and SB was able to completely block BMP2-induced HDPC differentiation. Bar = 100 μm. ALPase, alkaline phosphatase; BMP, bone morphogenetic protein; DAPI, diamidino-phenyl-indole; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HDPC, human dental pulp cell; qPCR, quantitative polymerase chain reaction.
Figure 3 Blockade of the p38 signalling pathway can reduce the BMP2-induced activation of WNT/β-catenin signalling and cell differentiation. (a) After starvation for 2 h, pretreatment with 30 µmol·L−1 SB203580 for 2 h, and then stimulation of HDPCs with 30 ng·mL−1 rhBMP2 for various time periods; SB203580 treatment blocks the activation of β-catenin by BMP2. (b) After 6 h, immunofluorescence staining showed that SB203580 treatment reduces the translocation of β-catenin by BMP. Bar = 50 μm. (c) After 24 h, qPCR showed that SB203580 treatment reduces the expression of lef1 mRNA. (d) Treatment with Noggin, LDN or SB partially blocks BMP2-induced HDPC differentiation, whereas combined treatment with LDN and SB was able to completely block BMP2-induced HDPC differentiation. Bar = 100 μm. ALPase, alkaline phosphatase; BMP, bone morphogenetic protein; DAPI, diamidino-phenyl-indole; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HDPC, human dental pulp cell; qPCR, quantitative polymerase chain reaction.CC BY-NC-SA · PubMed Central
Figure 4 p38 MAPK signalling plays a role in BMP2-WNT3a-induced β-catenin signalling activation and cell differentiation. (a) A TOPflash dual luciferase assay reveals that SB203580 treatment can attenuate the effects of WNT3a, BMP2, or even BMP2 together with WNT3a. (b and c) ALPase staining and ARS staining reveal a synergistic effect of BMP2 and WNT3a on HDPC differentiation, and SB203580 treatment can attenuate the function of BMP2, even in the presence of WNT3a. BMP2 induces β-catenin expression and cell differentiation in HDPCs partly through the p38 MAPK pathway. Bar = 100 μm in b. ALPase, alkaline phosphatase; BMP, bone morphogenetic protein; DMSO, dimethyl sulfoxide; HDPC, human dental pulp cell.
Figure 4 p38 MAPK signalling plays a role in BMP2-WNT3a-induced β-catenin signalling activation and cell differentiation. (a) A TOPflash dual luciferase assay reveals that SB203580 treatment can attenuate the effects of WNT3a, BMP2, or even BMP2 together with WNT3a. (b and c) ALPase staining and ARS staining reveal a synergistic effect of BMP2 and WNT3a on HDPC differentiation, and SB203580 treatment can attenuate the function of BMP2, even in the presence of WNT3a. BMP2 induces β-catenin expression and cell differentiation in HDPCs partly through the p38 MAPK pathway. Bar = 100 μm in b. ALPase, alkaline phosphatase; BMP, bone morphogenetic protein; DMSO, dimethyl sulfoxide; HDPC, human dental pulp cell.CC BY-NC-SA · PubMed Central

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Metadata

Authors
Yang, J., Ye, L., Hui, T.-Q., Yang, D.-M., Huang, D.-M., Zhou, X.-D., Mao, J. J., & Wang, C.-L.
Affiliations
  • Sichuan University (CN)
  • Columbia University Irving Medical Center (US)
ORCID
Venue
International Journal of Oral Science
Publisher
Springer Science and Business Media LLC
Published
2015-06
Volume
7
Issue
2
Pages
95-102
ISSN
  • 1674-2818 (ISSN-L)
  • 2049-3169
DOI
10.1038/ijos.2015.7
PMC
PMC4817555
OpenAlex
W2408014337
Cited by
68
References
0
Citations by year
2026: 5 · 2025: 5 · 2024: 6 · 2023: 7 · 2022: 4 · 2021: 9 · 2020: 7 · 2019: 5 · 2018: 5 · 2017: 7 · 2016: 7 · 2015: 1
FWCI
2.90
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Oral Science (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (813220170, 81070801, 81200759)
  • Education Department of Sichuan Province (13TD0038)
  • Sichuan Province Science and Technology Support Program
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Dentistry › Oral Surgery › Endodontics and Root Canal Treatments
  • Health Sciences › Dentistry › General Dentistry › dental development and anomalies
Keywords
BMP-2, Wnt/β-catenin signaling, p38 MAPK, human dental pulp cells, odontoblast differentiation, dentin formation, pulp repair, β-catenin, SB203580, noggin, LDN-193189
MeSH terms
Cell Differentiation, Dental Pulp, Humans, MAP Kinase Signaling System, Wnt Proteins, beta Catenin, Bone Morphogenetic Protein 2

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