Tooth eruption is a unique biological process by which highly mineralized tissues emerge into the outer world, and it occurs concomitantly with tooth root formation. These 2 processes have been considered independent phenomena; however, recent studies support the theory that they are indeed intertwined. Dental mesenchymal progenitor cells in the dental follicle lie at the heart of the coupling of these 2 processes, providing a source for diverse mesenchymal cells that support formation of the highly functional tooth root and the periodontal attachment apparatus, while facilitating formation of osteoclasts. These cells are regulated by autocrine signaling by parathyroid hormone–related protein (PTHrP) and its parathyroid hormone/PTHrP receptor PPR. This PTHrP-PPR signaling appears to crosstalk with other signaling pathways and regulates proper cell fates of mesenchymal progenitor cell populations. Disruption of this autocrine PTHrP-PPR signaling in these cells leads to defective formation of the periodontal attachment apparatus, tooth root malformation, and failure of tooth eruption in molars, which essentially recapitulate primary failure of eruption in humans, a rare genetic disorder exclusively affecting tooth eruption. Diversity and distinct functionality of these mesenchymal progenitor cell populations that regulate tooth eruption and tooth root formation are beginning to be unraveled.
AbergTWozneyJThesleffI. 1997. Expression patterns of bone morphogenetic proteins (Bmps) in the developing mouse tooth suggest roles in morphogenesis and cell differentiation. Dev Dyn. 210(4):383–396.
AlfaqeehSOralovaVFoxworthyMMatalovaEGrigoriadisAETuckerAS. 2015. Root and eruption defects in c-Fos mice are driven by loss of osteoclasts. J Dent Res. 94(12):1724–1731.
4.
AsagiriMTakayanagiH. 2007. The molecular understanding of osteoclast differentiation. Bone. 40(2):251–264.
5.
BaccettiT. 2000. Tooth anomalies associated with failure of eruption of first and second permanent molars. Am J Orthod Dentofacial Orthop. 118(6):608–610.
6.
BaiYBaiYMatsuzakaKHashimotoSFukuyamaTWuLMiwaTLiuXWangXInoueT. 2011. Cementum- and periodontal ligament-like tissue formation by dental follicle cell sheets co-cultured with Hertwig’s epithelial root sheath cells. Bone. 48(6):1417–1426.
7.
BalicAThesleffI. 2015. Tissue interactions regulating tooth development and renewal. Curr Top Dev Biol. 115:157–186.
8.
BeedermanMLamplotJDNanGWangJLiuXYinLLiRShuiWZhangHKimSH, et al. 2013. Bmp signaling in mesenchymal stem cell differentiation and bone formation. J Biomed Sci Eng. 6(8A):32–52.
9.
BriscoeJTherondPP. 2013. The mechanisms of hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol. 14(7):416–429.
10.
BruggerSMMerrillAETorres-VazquezJWuNTingMCChoJYDobiasSLYiSELyonsKBellJR, et al. 2004. A phylogenetically conserved cis-regulatory module in the Msx2 promoter is sufficient for BMP-dependent transcription in murine and drosophila embryos. Development. 131(20):5153–5165.
11.
CahillDRMarksSCJr.1980. Tooth eruption: evidence for the central role of the dental follicle. J Oral Pathol. 9(4):189–200.
12.
ChaiYJiangXItoYBringasPHanJRowitchDHSorianoPMcMahonAPSucovHM. 2000. Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis. Development. 127(8):1671–1679.
13.
ChuangPTMcMahonAP. 1999. Vertebrate hedgehog signalling modulated by induction of a hedgehog-binding protein. Nature. 397(6720):617–621.
14.
CongQXuRYangY. 2019. Galphas signaling in skeletal development, homeostasis and diseases. Curr Top Dev Biol. 133:281–307.
15.
DassuleHRLewisPBeiMMaasRMcMahonAP. 2000. Sonic hedgehog regulates growth and morphogenesis of the tooth. Development. 127(22):4775–4785.
16.
DeanTVilardagaJPPottsJTGardellaTJ. 2008. Altered selectivity of parathyroid hormone (PTH) and pth-related protein (PTHrP) for distinct conformations of the PTH/PTHrP receptor. Mol Endocrinol. 22(1):156–166.
17.
DeckerEStellzig-EisenhauerAFiebigBSRauCKressWSaarKRuschendorfFHubnerNGrimmTWeberBH. 2008. PTHR1 loss-of-function mutations in familial, nonsyndromic primary failure of tooth eruption. Am J Hum Genet. 83(6):781–786.
18.
FleischmannovaJMatalovaESharpePTMisekIRadlanskiRJ. 2010. Formation of the tooth-bone interface. J Dent Res. 89(2):108–115.
Frazier-BowersSAHendricksHMWrightJTLeeJLongKDibbleCFBencharitS. 2014. Novel mutations in PTH1R associated with primary failure of eruption and osteoarthritis. J Dent Res. 93(2):134–139.
21.
Frazier-BowersSASimmonsDWrightJTProffitWRAckermanJL. 2010. Primary failure of eruption and PTH1R: the importance of a genetic diagnosis for orthodontic treatment planning. Am J Orthod Dentofacial Orthop. 137(2):160.e161–e167.
22.
GeGGreenspanDS. 2006. Developmental roles of the BMP1/TLD metalloproteinases. Birth Defects Res C Embryo Today. 78(1):47–68.
23.
GlassDA2ndBialekPAhnJDStarbuckMPatelMSCleversHTaketoMMLongFMcMahonAPLangRA, et al. 2005. Canonical wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell. 8(5):751–764.
24.
GorskiJPMarksSC. 1992. Current concepts of the biology of tooth eruption. Crit Rev Oral Biol Med. 3(3):185–206.
25.
GrippaudoCCafieroCD’ApolitoIRicciBFrazier-BowersSA. 2018. Primary failure of eruption: clinical and genetic findings in the mixed dentition. Angle Orthod. 88(3):275–282.
26.
HammerschmidtMBrookAMcMahonAP. 1997. The world according to hedgehog. Trends Genet. 13(1):14–21.
27.
HeinrichJBsoulSBarnesJWoodruffKAbboudS. 2005. CSF-1, RANKL and OPG regulate osteoclastogenesis during murine tooth eruption. Arch Oral Biol. 50(10):897–908.
28.
HolmenSLZylstraCRMukherjeeASiglerREFaugereMCBouxseinMLDengLClemensTLWilliamsBO. 2005. Essential role of beta-catenin in postnatal bone acquisition. J Biol Chem. 280(22):21162–21168.
29.
HuangHWangJZhangYZhuGLiYPPingJChenW. 2018. Bone resorption deficiency affects tooth root development in RANKL mutant mice due to attenuated IGF-1 signaling in radicular odontoblasts. Bone. 114:161–171.
30.
InghamPWMcMahonAP. 2001. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15(23):3059–3087.
31.
JelaniMKangCMohamoudHSAl-RehailiRAlmramhiMMSerafiRYangHAl-AamaJYNaeemMAlkhiaryYM. 2016. A novel homozygous PTH1R variant identified through whole-exome sequencing further expands the clinical spectrum of primary failure of tooth eruption in a consanguineous Saudi family. Arch Oral Biol. 67:28–33.
32.
JernvallJThesleffI. 2000. Reiterative signaling and patterning during mammalian tooth morphogenesis. Mech Dev. 92(1):19–29.
33.
JüppnerHAbou-SamraABFreemanMKongXFSchipaniERichardsJKolakowskiLFHockJPottsJTKronenbergHM. 1991. A G protein–linked receptor for parathyroid hormone and parathyroid hormone–related peptide. Science. 254(5034):1024–1026.
34.
KaraplisACHeBNguyenMTYoungIDSemeraroDOzawaHAmizukaN. 1998. Inactivating mutation in the human parathyroid hormone receptor type 1 gene in Blomstrand chondrodysplasia. Endocrinology. 139(12):5255–5258.
35.
KhanMSeppalaMZoupaMCobourneMT. 2007. Hedgehog pathway gene expression during early development of the molar tooth root in the mouse. Gene Expr Patterns. 7(3):239–243.
36.
KimTHBaeCHJangEHYoonCYBaeYKoSOTaketoMMChoES. 2012. Col1a1-cre mediated activation of beta-catenin leads to aberrant dento-alveolar complex formation. Anat Cell Biol. 45(3):193–202.
37.
KimTHBaeCHLeeJCKimJEYangXde CrombruggheBChoES. 2015. Osterix regulates tooth root formation in a site-specific manner. J Dent Res. 94(3):430–438.
38.
KimTHBaeCHLeeJCKoSOYangXJiangRChoES. 2013. Beta-catenin is required in odontoblasts for tooth root formation. J Dent Res. 92(3):215–221.
KimTHLeeJYBaekJALeeJCYangXTaketoMMJiangRChoES. 2011. Constitutive stabilization of β-catenin in the dental mesenchyme leads to excessive dentin and cementum formation. Biochem Biophys Res Commun. 412(4):549–555.
41.
KjaerI. 2014. Mechanism of human tooth eruption: review article including a new theory for future studies on the eruption process. Scientifica (Cairo). 2014:341905.
42.
KozhemyakinaECohenTYaoTPLassarAB. 2009. Parathyroid hormone-related peptide represses chondrocyte hypertrophy through a protein phosphatase 2A/histone deacetylase 4/MEF2 pathway. Mol Cell Biol. 29(21):5751–5762.
43.
KramerIHalleuxCKellerHPegurriMGooiJHWeberPBFengJQBonewaldLFKneisselM. 2010. Osteocyte Wnt/beta-catenin signaling is required for normal bone homeostasis. Mol Cell Biol. 30(12):3071–3085.
44.
KronenbergHM. 2003. Developmental regulation of the growth plate. Nature. 423(6937):332–336.
45.
KronenbergHM. 2006. PTHRP and skeletal development. Ann NY Acad Sci. 1068:1–13.
46.
LiJParadaCChaiY. 2017. Cellular and molecular mechanisms of tooth root development. Development. 144(3):374–384.
LoganCYNusseR. 2004. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 20:781–810.
49.
LuXRiosHFJiangBXingLKadlcekRGreenfieldEMLuoGFengJQ. 2009. A new osteopetrosis mutant mouse strain (NTL) with odontoma-like proliferations and lack of tooth roots. Eur J Oral Sci. 117(6):625–635.
50.
MannstadtMJuppnerHGardellaTJ. 1999. Receptors for PTH and PTHRP: their biological importance and functional properties. Am J Physiol. 277(5):F665–F675.
51.
MarksSCJrSchroederHE. 1996. Tooth eruption: theories and facts. Anat Rec. 245(2):374–393.
52.
MizuhashiKOnoWMatsushitaYSakagamiNTakahashiASaundersTLNagasawaTKronenbergHMOnoN. 2018. Resting zone of the growth plate houses a unique class of skeletal stem cells. Nature. 563(7730):254–258.
53.
NakashimaTHayashiMFukunagaTKurataKOh-HoraMFengJQBonewaldLFKodamaTWutzAWagnerEF, et al. 2011. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med. 17(10):1231–1234.
54.
NakatomiMMoritaIEtoKOtaMS. 2006. Sonic hedgehog signaling is important in tooth root development. J Dent Res. 85(5):427–431.
55.
NanciA. 2017. Ten Cate’s oral histology—e-book: development, structure, and function. St. Louis (MO): Elsevier Health Sciences.
56.
NishimoriSO’MearaMJCastroCNodaHCetinbasMda Silva MartinsJAyturkUBrooksDJBruceMNagataM, et al. 2019. Salt-inducible kinases dictate parathyroid hormone receptor action in bone development and remodeling. J Clin Invest. 2019:130126.
57.
OnoWSakagamiNNishimoriSOnoNKronenbergHM. 2016. Parathyroid hormone receptor signalling in osterix-expressing mesenchymal progenitors is essential for tooth root formation. Nat Commun. 7:11277.
58.
PhilbrickWMDreyerBENakchbandiIAKaraplisAC. 1998. Parathyroid hormone–related protein is required for tooth eruption. Proc Natl Acad Sci U S A. 95(20):11846–11851.
59.
ProffitWRVigKW. 1981. Primary failure of eruption: a possible cause of posterior open-bite. Am J Orthod. 80(2):173–190.
60.
RakianAYangWCGluhak-HeinrichJCuiYHarrisMAVillarrealDFengJQMacdougallMHarrisSE. 2013. Bone morphogenetic protein-2 gene controls tooth root development in coordination with formation of the periodontium. Int J Oral Sci. 5(2):75–84.
61.
RichmanJM. 2019. Shedding new light on the mysteries of tooth eruption. Proc Natl Acad Sci U S A. 116(2):353–355.
62.
RisomLChristoffersenLDaugaard-JensenJHoveHDAndersenHSAndresenBSKreiborgSDunoM. 2013. Identification of six novel PTH1R mutations in families with a history of primary failure of tooth eruption. PLoS One. 8(9):e74601.
63.
RothHFritscheLGMeierCPilzPEigenthalerMMeyer-MarcottyPStellzig-EisenhauerAProffPKannoCMWeberBH. 2014. Expanding the spectrum of PTH1R mutations in patients with primary failure of tooth eruption. Clin Oral Investig. 18(2):377–384.
64.
SakagamiNMatsushitaYSyklawer-HowleSKronenbergHMOnoWOnoN. 2018. Msx2 marks spatially restricted populations of mesenchymal precursors. J Dent Res. 97(11):1260–1267.
65.
SchipaniEKruseKJuppnerH. 1995. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science. 268(5207):98–100.
66.
SembaINonakaKTakahashiITakahashiKDashnerRShumLNuckollsGHSlavkinHC. 2000. Positionally-dependent chondrogenesis induced by BMP4 is co-regulated by Sox9 and Msx2. Dev Dyn. 217(4):401–414.
Steele-PerkinsGButzKGLyonsGEZeichner-DavidMKimHJChoMIGronostajskiRM. 2003. Essential role for NFI-C/CTF transcription-replication factor in tooth root development. Mole Cell Biol. 23(3):1075–1084.
69.
TakahashiANagataMGuptaAMatsushitaYYamaguchiTMizuhashiKMakiKRuellasACCevidanesLSKronenbergHM, et al. 2019. Autocrine regulation of mesenchymal progenitor cell fates orchestrates tooth eruption. Proc Natl Acad Sci U S A. 116(2):575–580.
70.
Ten CateAR. 1997. The development of the periodontium—a largely ectomesenchymally derived unit. Periodontol2000. 13:9–19.
VasavadaRCCavaliereCD’ErcoleAJDannPBurtisWJMadlenerALZawalichKZawalichWPhilbrickWStewartAF. 1996. Overexpression of parathyroid hormone-related protein in the pancreatic islets of transgenic mice causes islet hyperplasia, hyperinsulinemia, and hypoglycemia. J Biol Chem. 271(2):1200–1208.
WangJMuirAMRenYMassoudiDGreenspanDSFengJQ. 2017. Essential roles of bone morphogenetic protein-1 and mammalian tolloid-like 1 in postnatal root dentin formation. J Endod. 43(1):109–115.
75.
WangXP. 2013. Tooth eruption without roots. J Dent Res. 92(3):212–214.
76.
WangYCoxMKCoricorGMacDougallMSerraR. 2013. Inactivation of Tgfbr2 in Osterix-Cre expressing dental mesenchyme disrupts molar root formation. Dev Biol. 382(1):27–37.
77.
WiseGEFrazier-BowersSD’SouzaRN. 2002. Cellular, molecular, and genetic determinants of tooth eruption. Crit Rev Oral Biol Med. 13(4):323–334.
78.
WiseGEKingGJ. 2008. Mechanisms of tooth eruption and orthodontic tooth movement. J Dent Res. 87(5):414–434.
79.
WuMChenGLiYP. 2016. TGF-beta and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 4:16009.
80.
WuYYuanXPerezKCHymanSWangLPellegriniGSalmonBBellidoTHelmsJA. 2019. Aberrantly elevated Wnt signaling is responsible for cementum overgrowth and dental ankylosis. Bone. 122:176–183.
81.
WysolmerskiJJBroadusAEZhouJFuchsEMilstoneLMPhilbrickWM. 1994. Overexpression of parathyroid hormone-related protein in the skin of transgenic mice interferes with hair follicle development. Proc Natl Acad Sci U S A. 91(3):1133–1137.
82.
WysolmerskiJJMcCaughern-CarucciJFDaifotisAGBroadusAEPhilbrickWM. 1995. Overexpression of parathyroid hormone-related protein or parathyroid hormone in transgenic mice impairs branching morphogenesis during mammary gland development. Development. 121(11):3539–3547.
83.
XiongJOnalMJilkaRLWeinsteinRSManolagasSCO’BrienCA. 2011. Matrix-embedded cells control osteoclast formation. Nat Med. 17(10):1235–1241.
84.
XuJLamouilleSDerynckR. 2009. Tgf-beta-induced epithelial to mesenchymal transition. Cell Res. 19(2):156–172.
85.
YamaguchiTHosomichiKNaritaAShirotaTTomoyasuYMakiKInoueI. 2011. Exome resequencing combined with linkage analysis identifies novel PTH1R variants in primary failure of tooth eruption in Japanese. J Bone Miner Res. 26(7):1655–1661.
86.
YaoSPanFPrpicVWiseGE. 2008. Differentiation of stem cells in the dental follicle. J Dent Res. 87(8):767–771.
87.
YodaSSudaNKitaharaYKomoriTOhyamaK. 2004. Delayed tooth eruption and suppressed osteoclast number in the eruption pathway of heterozygous Runx2/Cbfa1 knockout mice. Arch Oral Biol. 49(6):435–442.
88.
ZhangHJiangYQinCLiuYHoSPFengJQ. 2015. Essential role of osterix for tooth root but not crown dentin formation. J Bone Miner Res. 30(4):742–746.
89.
ZhangJLiaoLLiYXuYGuoWTianWZouS. 2019. Parathyroid hormone-related peptide (1-34) promotes tooth eruption and inhibits osteogenesis of dental follicle cells during tooth development. J Cell Physiol. 234(7):11900–11911.
90.
ZhangPJobertASCouvineauASilveC. 1998. A homozygous inactivating mutation in the parathyroid hormone/parathyroid hormone-related peptide receptor causing blomstrand chondrodysplasia. J Clin Endocrinol Metab. 83(9):3365–3368.
91.
ZhaoHFengJSeidelKShiSKleinOSharpePChaiY. 2014. Secretion of Shh by a neurovascular bundle niche supports mesenchymal stem cell homeostasis in the adult mouse incisor. Cell Stem Cell. 14(2):160–173.
