Osterix Regulates Tooth Root Formation in a Site-specific Manner

Kim, T.H.; Bae, Cheol-Hyeon; Lee, J.C.; Kim, J.E.; Yang, Xu; Crombrugghe, Benoít de; Cho, E.S.

doi:10.1177/0022034514565647

Cited by 61 publications

(59 citation statements)

References 32 publications

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“…While these findings support Alpl +/A116T mice as a model of odontohypophosphatasia, limitations included lack of defects in dentin and enamel and a mildly affected periodontium. In dentoalveolar tissues, the Col1a1-Cre line targets gene ablation to type I collagen-producing cells, including odontoblasts, osteoblasts, cementoblasts, and fibroblasts (Dacquin et al 2002;Kim et al 2012;Kim et al 2015). Col1a1-cKO mice recapitulated an array of classic human and mouse HPP dental defects, including short molar roots, thin dentin, widened pulp chambers, lack of acellular cementum, loss of attachment, and hypomineralized alveolar bone.…”

Section: Dental Defects In Mouse Models Of Late-onset Hppmentioning

confidence: 99%

Conditional Alpl Ablation Phenocopies Dental Defects of Hypophosphatasia

et al. 2016

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Loss-of-function mutations in ALPL result in hypophosphatasia (HPP), an inborn error of metabolism that causes defective skeletal and dental mineralization. ALPL encodes tissue-nonspecific alkaline phosphatase, an enzyme expressed in bone, teeth, liver, and kidney that hydrolyzes the mineralization inhibitor inorganic pyrophosphate. As Alpl-null mice die before weaning, we aimed to generate mouse models of late-onset HPP with extended life spans by engineering a floxed Alpl allele, allowing for conditional gene ablation (conditional knockout [cKO]) when crossed with Cre recombinase transgenic mice. The authors hypothesized that targeted deletion of Alpl in osteoblasts and selected dental cells (Col1a1-cKO) or deletion in chondrocytes, osteoblasts, and craniofacial mesenchyme (Prx1-cKO) would phenocopy skeletal and dental manifestations of late-onset HPP. Col1a1-cKO and Prx1-cKO mice were viable and fertile, and they did not manifest the epileptic seizures characteristic of the Alpl-/- model of severe infantile HPP. Both cKO models featured normal postnatal body weight but significant reduction as compared with wild type mice by 8 to 12 wk. Plasma alkaline phosphatase for both cKO models at 24 wk was reduced by approximately 75% as compared with controls. Radiography revealed profound skeletal defects in cKO mice, including rachitic changes, hypomineralized long bones, deformations, and signs of fractures. Microcomputed tomography confirmed quantitative differences in cortical and trabecular bone, including decreased cortical thickness and mineral density. Col1a1-cKO mice exhibited classic signs of HPP dentoalveolar disease, including short molar roots with thin dentin, lack of acellular cementum, and osteoid accumulation in alveolar bone. Prx1-cKO mice exhibited the same array of periodontal defects but featured less affected molar dentin. Both cKO models exhibited reduced alveolar bone height and 4-fold increased numbers of osteoclast-like cells versus wild type at 24 wk, consistent with HPP-associated periodontal disease. These novel models of late-onset HPP can inform on long-term skeletal and dental manifestations and will provide essential tools to further studies of etiopathologies and therapeutic interventions.

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Section: Dental Defects In Mouse Models Of Late-onset Hppmentioning

confidence: 99%

Conditional Alpl Ablation Phenocopies Dental Defects of Hypophosphatasia

et al. 2016

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“…Kim et al . () also investigated the effects of odontoblast‐specific inactivation of Osx . They confirmed that mutant mice displayed normal crowns but short molar roots and thin inter‐radicular dentine; the root elongation was also disturbed by impaired odontoblastic maturation.…”

Section: Site‐specific Function Of Osx In Root Formationmentioning

confidence: 99%

“…, Kim et al . ). First recognized in bone development, these genes participate in both the processes of osteogenesis and odontogenesis that share many common characteristics in the regulation mechanisms (Nakashima et al .…”

Section: Introductionmentioning

confidence: 97%

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Site‐specific function and regulation of Osterix in tooth root formation

Sui

et al. 2016

Int Endodontic J

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Congenital diseases of tooth roots, in terms of developmental abnormalities of short and thin root phenotypes, can lead to loss of teeth. A more complete understanding of the genetic molecular pathways and biological processes controlling tooth root formation is required. Recent studies have revealed that Osterix (Osx), a key mesenchymal transcriptional factor participating in both the processes of osteogenesis and odontogenesis, plays a vital role underlying the mechanisms of developmental differences between root and crown. During tooth development, Osx expression has been identified from late embryonic to postnatal stages when the tooth root develops, particularly in odontoblasts and cementoblasts to promote their differentiation and mineralization. Furthermore, the site-specific function of Osx in tooth root formation has been confirmed, because odontoblastic Osx-conditional knockout mice demonstrate primarily short and thin root phenotypes with no apparent abnormalities in the crown (Journal of Bone and Mineral Research 30, 2014 and 742, Journal of Dental Research 94, 2015 and 430). These findings suggest that Osx functions to promote odontoblast and cementoblast differentiation and root elongation only in root, but not in crown formation. Mechanistic research shows regulatory networks of Osx expression, which can be controlled through manipulating the epithelial BMP signalling, mesenchymal Runx2 expression and cellular phosphorylation levels, indicating feasible routes of promoting Osx expression postnatally (Journal of Cellular Biochemistry 114, 2013 and 975). In this regard, a promising approach might be available to regenerate the congenitally diseased root and that regenerative therapy would be the best choice for patients with developmental tooth diseases.

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“…We appreciate the letter to the editor from Dr. Feng in response to our article titled "Osterix Regulates Tooth Root Formation in a Site-specific Manner" (Kim et al 2015).…”

Section: Letters To the Editormentioning

confidence: 99%

Response to Letter to the Editor, “Osterix Regulates Tooth Root Formation in a Site-specific Manner”

2015

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Feng et al. 2015) in response to our article titled "Osterix Regulates Tooth Root Formation in a Site-specific Manner" (Kim et al. 2015).A major issue is raised from our interpretation about the localization of Osterix and dentin phenotypes of 2 independent conditional Osterix knockout mouse lines (Kim et al. 2015). Dr. Feng's group recently reported that Osterix has an essential role in tooth root but not crown dentin formation (Zhang et al. 2015). Regardless of the difference in transactivators, dentin phenotype seems to be similar in Osterix mutants of 2 reports.In our observation, Osterix mutant mice did not show remarkable dentin phenotype in crown but did exhibit severe impairment of interradicular dentin in molar roots. In this region, both dental mesenchyme and HERS proliferation was relatively lower than in the root elongation region. This finding indicates that Osterix plays a critical role in odontoblast differentiation in a site-specific manner. In this context, it is notable that "rootless" teeth are produced without crown defect in the tissue-specific β-catenin inactivation mice (Kim et al. 2013).We also examined tooth phenotype of Osterix null newborn mice (Appendix Fig.). Although crown morphogenesis was normal, differentiation of both odontoblasts and ameloblasts was disrupted as reported previously (Clarke et al. 2014). In addition, Osterix is known to be short-lived protein, easily sumoylated and ubiquitinated (Hosoya et al. 2013;Peng et al. 2013). It could be associated with the discrepancies in Osterix expression between mRNA and protein level.We hope that our finding could contribute to further understanding the principles underlying tooth root formation.

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Osterix Regulates Tooth Root Formation in a Site-specific Manner

Cited by 61 publications

References 32 publications

Conditional Alpl Ablation Phenocopies Dental Defects of Hypophosphatasia

Conditional Alpl Ablation Phenocopies Dental Defects of Hypophosphatasia

Site‐specific function and regulation of Osterix in tooth root formation

Response to Letter to the Editor, “Osterix Regulates Tooth Root Formation in a Site-specific Manner”

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