BMP‐Smad Signaling Regulates Postnatal Crown Dentinogenesis in Mouse Molar

Abstract

Dentinogenesis, a formation of dentin by odontoblasts, is an essential process during tooth development. Bone morphogenetic proteins (BMPs) are one of the most crucial growth factors that contribute to dentin formation. However, it is still unclear how BMP signaling pathways regulate postnatal crown and root dentinogenesis. BMPs transduce signals through canonical Smad and non‐Smad signaling pathways including p38 and ERK signaling pathways. To investigate the roles of Smad and non‐Smad signaling pathways in dentinogenesis, we conditionally deleted Bmpr1a, which encodes the type 1A receptor for BMPs, to remove both Smad and non‐Smad pathways in Osterix‐expressing cells. We also expressed a constitutively activated form of Bmpr1a (caBmpr1a) to increase Smad1/5/9 signaling activity without altered non‐Smad activity in odontoblasts. To understand the function of BMP signaling during postnatal dentin formation, Cre activity was induced at the day of birth. Our results showed that loss of BmpR1A in odontoblasts resulted in impaired dentin formation and short molar roots at postnatal day 21. Bmpr1a cKO mice displayed a reduction of dentin matrix production compared to controls associated with increased cell proliferation and reduced Osx and Dspp expression. In contrast, caBmpr1a mutant mice that show increased Smad1/5/9 signaling activity resulted in no overt tooth phenotype. To further dissect the functions of each signaling activity, we generated Bmpr1a cKO mice also expressing caBmpr1a to restore only Smad1/5/9 signaling activity. Restoring Smad activity in the compound mutant mice rescued impaired crown dentin formation in the Bmpr1a cKO mice; however, impaired root dentin formation and short roots were not changed. These results suggest that BMP‐Smad signaling in odontoblasts is responsible for crown dentin formation, while non‐Smad signaling may play a major role in root dentin formation and elongation. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Epiprofin Transcriptional Activation Promotes Ameloblast Induction From Mouse Induced Pluripotent Stem Cells via the BMP-Smad Signaling Axis

“…Since epithelial Epfn overexpression also causes bilateral ameloblast differentiation and enamel formation in mouse incisor ( Nakamura et al, 2017 ), we determined whether Epfn activation promoted ameloblast induction from iPSCs by regulating the BMP-Smad pathway. Interestingly, we found that BMP-Smad activity, reflected by p-Smad1/5/8 expression ( Sartori et al, 2014 ; Omi et al, 2020 ), was upregulated after Epfn activation at stages 2 and 3. However, the mechanisms underlying the enhanced BMP-Smad pathway appeared to differ between stages 2 and 3.…”

USP34 regulates tooth root morphogenesis by stabilizing NFIC

“… 23 , 39 Bmp signaling is found activated when dental mesenchymal cells start differentiating into odontoblasts, which initiates apical growth of root. 40 , 41 It has also been confirmed that epithelial Wnt10a controls root furcation formation and regulates proliferation of adjacent mesenchymal cells. 10 Upregulation of Wnt signaling by ablation of Runx2 would disturb normal odontoblastic differentiation.…”

Loss of BMP2 and BMP4 Signaling in the Dental Epithelium Causes Defective Enamel Maturation and Aberrant Development of Ameloblasts

“…Epithelial or mesenchymal loss of the gene encoding type 1 BMP receptor1a (Bmpr1a) cause tooth developmental arrest [ 105 , 106 ], and deactivation of the Bmp4 gene in the dental mesenchyme leads to aberrant tooth formation [ 107 ]. Deletion of the Bmpr1a gene in odontoblasts [ 108 ] and single or combined loss of Bmp2 and Bmp4 gene function in the odontoblast lineage result in abnormal dentin formation [ 109 , 110 , 111 ]. K14-CRE/Bmp2 f/f /Bmp4 f/f mice with disabled Bmp2 and Bmp4 genes in the dental epithelium display abnormal enamel maturation [ 58 ], and mice overexpressing the BMP inhibitor noggin in the dental epithelium exhibit an array of tooth anomalies, including enamel defects [ 112 , 113 ].…”