Disruption of <i>Tgfbr2</i> in Odontoblasts Leads to Aberrant Pulp Calcification

Ahn, Yu-Hyeon; Kim, T.H.; Choi, Hwajung; Bae, Cheol-Hyeon; Yang, Yeon-Mi; Baek, Ji Eun; Lee, J.C.; Cho, E.S.

doi:10.1177/0022034515577427

Cited by 19 publications

(32 citation statements)

References 24 publications

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“…In our cohort, only one patient with LDS1 exhibited a phenotype similar to dentinogenesis imperfecta resulting in the pathognomonic severe grey tooth discolouration. The involvement of TGF-β signalling in dentin development is supported by numerous mouse studies 26 39 40. Dentin is produced by odontoblasts that are part of the dental mesenchyme and are derived from neural crest cells.…”

Section: Discussionmentioning

confidence: 97%

Severity of oro-dental anomalies in Loeys-Dietz syndrome segregates by gene mutation

et al. 2020

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Background Loeys-Dietz syndrome (LDS), an autosomal dominant rare connective tissue disorder, has multisystemic manifestations, characterised by vascular tortuosity, aneurysms and craniofacial manifestations. Based on the associated gene mutations along the transforming growth factor-beta (TGF-β) pathway, LDS is presently classified into six subtypes. Methods We present the oro-dental features of a cohort of 40 patients with LDS from five subtypes. Results The most common oro-dental manifestations were the presence of a high-arched and narrow palate, and enamel defects. Other common characteristics included bifid uvula, submucous cleft palate, malocclusion, dental crowding and delayed eruption of permanent teeth. Both deciduous and permanent teeth had enamel defects in some individuals. We established a grading system to measure the severity of enamel defects, and we determined that the severity of the enamel anomalies in LDS is subtype-dependent. In specific, patients with TGF-β receptor II mutations (LDS2) presented with the most severe enamel defects, followed by patients with TGF-β receptor I mutations (LDS1). LDS2 patients had higher frequency of oro-dental deformities in general. Across all five subtypes, as well as within each subtype, enamel defects exhibited incomplete penetrance and variable expression, which is not associated with the location of the gene mutations. Conclusion This study describes, in detail, the oro-dental manifestations in a cohort of LDS, and we conclude that LDS2 has the most severely affected phenotype. This extensive characterisation, as well as some identified distinguishing features can significantly aid dental and medical care providers in the diagnosis and clinical management of patients with this rare connective tissue disorder.

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Section: Discussionmentioning

confidence: 97%

Severity of oro-dental anomalies in Loeys-Dietz syndrome segregates by gene mutation

et al. 2020

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“…Further research is necessary to determine which signals and the precise timing required to promote axonogenesis and/or guide the axons to their appropriate targets during tooth innervation. A previous study demonstrated that the conditional deletion of Tgfbr2 in odontoblasts led to disrupted matrix secretion that calcified and obliterated the pulp chamber with age (Ahn et al 2015). This indicated that Tgfbr2 is crucial to maintaining soft pulp tissue, including the neuronal structures contained in it.…”

Section: Discussionmentioning

confidence: 98%

Tgfbr2 in dental pulp cells guides sensory innervation in developing teeth

Barkley

Serra

Nguyen

et al. 2020

Preprint

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Transforming growth factor β (TGFβ) plays an important role in tooth morphogenesis and mineralization. Our laboratory established a mouse model in which Tgfbr2 was conditionally deleted in the dental pulp (DP) mesenchyme using an Osterix promoter-driven Cre recombinase (Tgfbr2 cko ). These mice survived postnatally, but had significant defects in bones and teeth, including reduced mineralization and short roots. H&E staining revealed reduced axon-like structures in the mutant mice. Reporter imaging demonstrated that Osterix-Cre activity was localized within the tooth and was active in the DP and derivatives, but not in neurons. Previous research has established that paracrine signals from the dental pulp attract trigeminal axons toward and into the tooth during postnatal development, yet very little is known about the signals that regulate tooth innervation. Immunofluorescent staining for a neuronal marker, β3 tubulin, was performed on serial cryosections from control and mutant molars at two different postnatal stages. Confocal imaging and pixel quantification of β3 tubulin demonstrated reduced innervation in P7 and P24 Tgfbr2 cko first molars compared to controls, indicating that the signals necessary to promote neurite outgrowth were disrupted by Tgfbr2 deletion. Quantitative real time PCR showed that the mRNA expression levels of several neuronal genes were reduced. Lastly, trigeminal neurons were co-cultured atop Transwell filters overlying primary Tgfbr2 f/f DP cells. Tgfbr2 in the DP was deleted with an adenovirus expressing Cre recombinase. Confocal imaging of axons through the filter pores showed increased axonal sprouting from neurons cultured in the presence of Tgfbr2-positive DP cells compared to neurons cultured alone. Further, axon sprouting was reduced when Tgfbr2 was knocked down in the DP cells. These results indicate that Tgfbr2 in the DP mesenchyme regulates paracrine signals that guide sensory innervation of the tooth.Note: A list of abbreviations is included in the appendix.

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“…Odontoblast-specific disruption of Smad4 using Col1a1 -, Osteocalcin -, and Dspp -Cre resulted in gradual impairment of secondary dentin formation 38 . In addition, disruption of Tgfbr2 in odontoblasts leads to severe impairment of secondary dentin formation with idiopathic pulpal calcification 39 . Similarly, disruption of Bmpr1a in odontoblasts leads to secondary dentin defects without idiopathic pulpal calcification 39 .…”

Section: Discussionmentioning

confidence: 99%

“…In addition, disruption of Tgfbr2 in odontoblasts leads to severe impairment of secondary dentin formation with idiopathic pulpal calcification 39 . Similarly, disruption of Bmpr1a in odontoblasts leads to secondary dentin defects without idiopathic pulpal calcification 39 . Both these reports and our results suggest that progerin disturbs critical signaling involved in odontogenesis collectively required for proper secondary dentin formation.…”

Section: Discussionmentioning

confidence: 99%

Expression of the Hutchinson-Gilford Progeria Mutation Leads to Aberrant Dentin Formation

Choi

Kim

Jeong

et al. 2018

Sci Rep

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Hutchinson-Gilford progeria syndrome (HGPS) is a rare accelerated senescence disease, manifesting dental abnormalities and several symptoms suggestive of premature aging. Although irregular secondary dentin formation in HGPS patients has been reported, pathological mechanisms underlying aberrant dentin formation remain undefined. In this study, we analyzed the mandibular molars of a tissue-specific mouse model that overexpresses the most common HGPS mutation (LMNA, c.1824C > T, p.G608G) in odontoblasts. In the molars of HGPS mutant mice at postnatal week 13, targeted expression of the HGPS mutation in odontoblasts results in excessive dentin formation and pulp obliteration. Circumpulpal dentin of HGPS mutants was clearly distinguished from secondary dentin of wild-type (WT) littermates and its mantle dentin by considering the irregular porous structure and loss of dentinal tubules. However, the dentin was significantly thinner in the molars of HGPS mutants at postnatal weeks 3 and 5 than in those of WT mice. In vitro analyses using MDPC-23, a mouse odontoblastic cell line, showed cellular senescence, defects of signaling pathways and consequential downregulation of matrix protein expression in progerin-expressing odontoblasts. These results indicate that expression of the HGPS mutation in odontoblasts disturbs physiological secondary dentin formation. In addition, progerin-expressing odontoblasts secrete paracrine factors that can stimulate odontogenic differentiation of dental pulp cells. Taken together, our results suggest that the aberrant circumpulpal dentin of HGPS mutants results from defects in physiological secondary dentin formation and consequential pathologic response stimulated by paracrine factors from neighboring progerin-expressing odontoblasts.

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Disruption of Tgfbr2 in Odontoblasts Leads to Aberrant Pulp Calcification

Cited by 19 publications

References 24 publications

Severity of oro-dental anomalies in Loeys-Dietz syndrome segregates by gene mutation

Severity of oro-dental anomalies in Loeys-Dietz syndrome segregates by gene mutation

Tgfbr2 in dental pulp cells guides sensory innervation in developing teeth

Expression of the Hutchinson-Gilford Progeria Mutation Leads to Aberrant Dentin Formation

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