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

Abstract

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.

Keywords

human dental pulp cells / bone morphogenetic protein 2 / β-catenin / cell differentiation / p38

References

[1] Mao JJ, Robey PG, Prockop DJ. Stem cells in the face: tooth regeneration and beyond. Cell Stem Cell, 2012, 11(3): 291-301.

[2] Gronthos S, Mankani M, Brahim J. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci USA, 2000, 97(25): 13625-13630.

[3] Mann LM, Lennon DP, Caplan AI. Cultured rat pulp cells have the potential to form bone, cartilage, and dentin in vivo. Biological mechanisms of tooth movement and craniofacial adaptation, 1996 Boston: Harvard Society of the Advancement of Orthodontics 7-10.

[4] Yildirim S, Fu SY, Kim K. Tooth regeneration: a revolution in stomatology and evolution in regenerative medicine. Int J Oral Sci, 2011, 3(3): 107-116.

[5] Peng L, Ye L, Zhou XD. Mesenchymal stem cells and tooth engineering. Int J Oral Sci, 2009, 1(1): 6-12.

[6] Sloan AJ, Smith AJ. Stem cells and the dental pulp: potential roles in dentine regeneration and repair. Oral Dis, 2007, 13(2): 151-157.

[7] Smith AJ, Lesot H. Induction and regulation of crown dentinogenesis: embryonic events as a template for dental tissue repair?. Crit Rev Oral Biol Med, 2001, 12(5): 425-437.

[8] Saito T, Ogawa M, Hata Y. Acceleration effect of human recombinant bone morphogenetic protein-2 on differentiation of human pulp cells into odontoblasts. J Endod, 2004, 30(4): 205-208.

[9] Qin W, Yang F, Deng R. Smad 1/5 is involved in bone morphogenetic protein-2-induced odontoblastic differentiation in human dental pulp cells. J Endod, 2012, 38(1): 66-71.

[10] Li J, Huang X, Xu X. SMAD4-mediated WNT signaling controls the fate of cranial neural crest cells during tooth morphogenesis. Development, 2011, 138(10): 1977-1989.

[11] Qin W, Liu P, Zhang R. JNK MAPK is involved in BMP2-induced odontoblastic differentiation of human dental pulp cells. Connect Tissue Res, 2014, 55(3): 217-224.

[12] Nakashima M. Bone morphogenetic proteins in dentin regeneration for potential use in endodontic therapy. Cytokine Growth Factor Rev, 2005, 16(3): 369-376.

[13] Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors, 2004, 22(4): 233-241.

[14] Nakashima M, Reddi AH. The application of bone morphogenetic proteins to dental tissue engineering. Nat Biotechnol, 2003, 21(9): 1025-1032.

[15] Gautschi OP, Frey SP, Zellweger R. Bone morphogenetic proteins in clinical applications. ANZ J Surg, 2007, 77(8): 626-631.

[16] Bègue-Kirn C, Smith AJ, Loriot M. Comparative analysis of TGF beta s, BMPs, IGF1, msxs, fibronectin, osteonectin and bone sialoprotein gene expression during normal and in vitro-induced odontoblast differentiation. Int J Dev Biol, 1994, 38(3): 405-420.

[17] Iohara K, Nakashima M, Ito M. Dentin regeneration by dental pulp stem cell therapy with recombinant human bone morphogenetic protein 2. J Dent Res, 2004, 83(8): 590-595.

[18] Yang W, Harris MA, Cui Y. BMP2 is required for odontoblast differentiation and pulp vasculogenesis. J Dent Res, 2012, 91(1): 58-64.

[19] Chen J, Lan Y, Baek JA. Wnt/beta-catenin signaling plays an essential role in activation of odontogenic mesenchyme during early tooth development. Dev Biol, 2009, 334(1): 174-185.

[20] Tamura M, Nemoto E, Sato MM. Role of the Wnt signaling pathway in bone and tooth. Front Biosci: Elite Ed, 2010, 2: 1405-1413.

[21] Mbalaviele G, Sheikh S, Stains JP. Beta-catenin and BMP2 synergize to promote osteoblast differentiation and new bone formation. J Cell Biochem, 2005, 94(2): 403-418.

[22] Chen D, Harris MA, Rossini G. Bone morphogenetic protein 2 (BMP2) enhances BMP3, BMP4, and bone cell differentiation marker gene expression during the induction of mineralized bone matrix formation in cultures of fetal rat calvarial osteoblasts. Calcif Tissue Int, 1997, 60(3): 283-290.

[23] Chen D, Ji X, Harris MA. Differential roles for bone morphogenetic protein (BMP) receptor type IB and IA in differentiation and specification of mesenchymal precursor cells to osteoblast and adipocyte lineages. J Cell Biol, 1998, 142(1): 295-305.

[24] Zhao M, Harris SE, Horn D. Bone morphogenetic protein receptor signaling is necessary for normal murine postnatal bone formation. J Cell Biol, 2002, 157(6): 1049-1060.

[25] Rawadi G, Vayssière B, Dunn F. BMP2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop. J Bone Miner Res, 2003, 18(10): 1842-1853.

[26] Zhang M, Yan Y, Lim YB. BMP2 modulates beta-catenin signaling through stimulation of Lrp5 expression and inhibition of beta-TrCP expression in osteoblasts. J Cell Biochem, 2009, 108(4): 896-905.

[27] Scheller EL, Chang J, Wang CY. Wnt/beta-catenin inhibits dental pulp stem cell differentiation. J Dent Res, 2008, 87(2): 126-130.

[28] Silvério KG, Davidson KC, James RG. Wnt/β-catenin pathway regulates bone morphogenetic protein (BMP2)-mediated differentiation of dental follicle cells. J Periodont Res, 2012, 47(3): 309-319.

[29] Hildesheim J, Salvador JM, Hollander MC. Casein kinase 2- and protein kinase A-regulated adenomatous polyposis coli and beta-catenin cellular localization is dependent on p38 MAPK. J Biol Chem, 2005, 280(17): 17221-17226.

[30] Bikkavilli RK, Feigin ME, Malbon CC. G alpha o mediates WNT-JNK signaling through dishevelled 1 and 3, RhoA family members, and MEKK 1 and 4 in mammalian cells. J Cell Sci, 2008, 121(Pt 2): 234-245.

[31] Caverzasio J, Manen D. Essential role of Wnt3a-mediated activation of mitogen-activated protein kinase p38 for the stimulation of alkaline phosphatase activity and matrix mineralization in C3H10T1/2 mesenchymal cells. Endocrinology, 2007, 148(11): 5323-5330.

[32] Keren A, Bengal E, Frank D. p38 MAP kinase regulates the expression of XMyf5 and affects distinct myogenic programs during Xenopus development. Dev Biol, 2005, 288(1): 73-86.

[33] Bikkavilli RK, Feigin ME, Malbon CC. p38 mitogen-activated protein kinase regulates canonical Wnt-beta-catenin signaling by inactivation of GSK3beta. J Cell Sci, 2008, 121(Pt 21): 3598-3607.

[34] Chang J, Sonoyama W, Wang Z. Noncanonical Wnt-4 signaling enhances bone regeneration of mesenchymal stem cells in craniofacial defects through activation of p38 MAPK. J Biol Chem, 2007, 282(42): 30938-30948.

[35] Jin EJ, Lee SY, Choi YA. BMP2-enhanced chondrogenesis involves p38 MAPK-mediated down-regulation of Wnt-7a pathway. Mol Cells, 2006, 22(3): 353-359.

[36] Couble ML, Farges JC, Bleicher F. Odontoblast differentiation of human dental pulp cells in explant cultures. Calcif Tissue Int, 2000, 66(2): 129-138.

[37] Han N, Zheng Y, Li R. β-catenin enhances odontoblastic differentiation of dental pulp cells through activation of Runx2. PLoS One, 2014, 9(2): e88890.

[38] Nakashima M, Nagasawa H, Yamada Y. Regulatory role of transforming growth factor-beta, bone morphogenetic protein-2, and protein-4 on gene expression of extracellular matrix proteins and differentiation of dental pulp cells. Dev Biol, 1994, 162(1): 18-28.

[39] Liu J, Jin T, Ritchie HH. In vitro differentiation and mineralization of human dental pulp cells induced by dentin extract. In Vitro Cell Dev Biol Anim, 2005, 41(7): 232-238.

[40] Zhang W, Walboomers XF, Wolke JG. Differentiation ability of rat postnatal dental pulp cells in vitro. Tissue Eng, 2005, 11(3/4): 357-368.

[41] Kido J, Ishida H, Nagata T. Effects of parathyroid hormone, 1,25-dihydroxyvitamin D3, and prostaglandin E2 on alkaline phosphatase activity in cultured dental pulp and gingiva cells of bovine calf. J Endod, 1991, 17(4): 161-164.

[42] Handrigan GR, Richman JM. A network of Wnt, hedgehog and BMP signaling pathways regulates tooth replacement in snakes. Dev Biol, 2010, 348(1): 130-141.

[43] Silvério KG, Davidson KC, James RG. Wnt/β-catenin pathway regulates bone morphogenetic protein (BMP2)-mediated differentiation of dental follicle cells. J Periodont Res, 2012, 47(3): 309-319.

[44] Kamiya N, Ye L, Kobayashi T. BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway. Development, 2008, 135(22): 3801-3811.

[45] Tang N, Song WX, Luo J. BMP9-induced osteogenic differentiation of mesenchymal progenitors requires functional canonical Wnt/beta-catenin signalling. J Cell Mol Med, 2009, 13(8B): 2448-2464.

[46] Nakashima A, Katagiri T, Tamura M. Cross-talk between Wnt and bone morphogenetic protein 2 (BMP2) signaling in differentiation pathway of C2C12 myoblasts. J Biol Chem, 2005, 280(45): 37660-37668.

[47] Hill TP, Später D, Taketo MM. Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell, 2005, 8(5): 727-738.

[48] Bain G, Müller T, Wang X. Activated beta-catenin induces osteoblast differentiation of C3H10T1/2 cells and participates in BMP2 mediated signal transduction. Biochem Biophys Res Commun, 2003, 301(1): 84-91.

[49] Semënov MV, Tamai K, Brott BK. Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr Biol, 2001, 11(12): 951-961.

[50] Mao B, Wu W, Li Y. LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature, 2001, 411(6835): 321-325.

[51] Xiao YT, Xiang LX, Shao JZ. Bone morphogenetic protein. Biochem Biophys Res Commun, 2007, 362(3): 550-553.

[52] Wu XB, Li Y, Schneider A. Impaired osteoblastic differentiation, reduced bone formation, and severe osteoporosis in noggin-overexpressing mice. J Clin Invest, 2003, 112(6): 924-934.

[53] Devlin RD, Du Z, Pereira RC. Skeletal overexpression of noggin results in osteopenia and reduced bone formation. Endocrinology, 2003, 144(5): 1972-1978.

[54] Hassel S, Schmitt S, Hartung A. Initiation of Smad-dependent and Smad-independent signaling via distinct BMP-receptor complexes. J Bone Joint Surg Am, 2003, 85(Suppl 3): 44-51.

[55] Rosen V. BMP2 signaling in bone development and repair. Cytokine Growth Factor Rev, 2009, 20(5/6): 475-480.

[56] Su Y, Xie W, Wang C. JNK/P38 mitogen-activated protein kinase used for hepatocyte growth factor-induced proliferation, differentiation, and migration in human dental papilla cells. J Endod, 2012, 38(9): 1207-1213.