The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Ariane Berdal - One of the best experts on this subject based on the ideXlab platform.
-
Sclerostin Deficiency Promotes Reparative Dentinogenesis.
Journal of dental research, 2017Co-Authors: Anne-margaux Collignon, Stéphane Simon, Ariane Berdal, Nawel Amri, Julie Lesieur, Jérémy Sadoine, Sandy Ribes, S. Menashi, Gaël Y. Rochefort, Catherine ChaussainAbstract:In humans, the SOST gene encodes sclerostin, an inhibitor of bone growth and remodeling, which also negatively regulates the bone repair process. Sclerostin has also been implicated in tooth formation, but its potential role in pulp healing remains unknown. The aim of this study was to explore the role of sclerostin in reparative Dentinogenesis using Sost knockout mice ( Sost-/-). The pulps of the first maxillary molars were mechanically exposed in 3-mo-old Sost-/- and wild-type (WT) mice ( n = 14 mice per group), capped with mineral trioxide aggregate cement, and the cavities were filled with a bonded composite resin. Reparative Dentinogenesis was dynamically followed up by micro-computed tomography and characterized by histological analyses. Presurgical analysis revealed a significantly lower pulp volume in Sost-/- mice compared with WT. At 30 and 49 d postsurgery, a large-forming reparative mineralized bridge, associated with osteopontin-positive mineralization foci, was observed in the Sost-/- pulps, whereas a much smaller bridge was detected in WT. At the longer time points, the bridge, which was associated with dentin sialoprotein-positive cells, had expanded in both groups but remained significantly larger in Sost-/- pulps. Sclerostin expression in the healing WT pulps was detected in the cells neighboring the forming dentin bridge. In vitro, mineralization induced by Sost-/- dental pulp cells (DPCs) was also dramatically enhanced when compared with WT DPCs. These observations were associated with an increased Sost expression in WT cells. Taken together, our data show that sclerostin deficiency hastened reparative Dentinogenesis after pulp injury, suggesting that the inhibition of sclerostin may constitute a promising therapeutic strategy for improving the healing of damaged pulps.
-
distorted patterns of Dentinogenesis and eruption in msx2 null mutants involvement of sost sclerostin
American Journal of Pathology, 2016Co-Authors: Nawel Amri, Stéphane Simon, Stephane X Djole, Stephane Petit, Sylvie Babajko, Amelie E Coudert, Beatriz Castaneda, Ariane BerdalAbstract:The muscle segment homeogenes Msx1 and Msx2 play a major role in tooth and bone formation. Periodontal osteoclast impairment also occurs in Msx2 null mutant mice, which is restored by overexpression of the receptor activator of NF-κB targeted in osteoclast lineage. Here, we investigated the role of Msx2 in Dentinogenesis. Experiments were performed on Msx2(-/-) mice and the MDPC-23 odontoblastic cell line. After Msx2 gene silencing, real-time quantitative RT-PCR data showed significant overexpression of Runx2, Bglap, Dspp, and Alpl. Of three inhibitors of Wnt/β-catenin signaling (Dkk1, SostDc1, and Sost/Sclerostin), only Sost was expressed in postnatal teeth and overexpressed in Msx2(-/-) tooth samples. Initial crown dentin formation-primary Dentinogenesis-occurred fairly normally in Msx2(-/-) teeth, albeit with distorted cusp patterns. Later stages of tooth development were characterized by a deviation from secondary toward tertiary Dentinogenesis with osteodentin formation and impaired dentin deposition leading to limited root elongation. In Msx2(-/-)/receptor activator of NF-κB-transgenic double mutants, the dentin phenotype, notably in the roots, was rescued and sclerostin levels were normalized. These data suggest that Msx2 may act indirectly on Dentinogenesis by controlling osteoclast activity and the signaling network related to eruption, supporting and further extending the concept that Msx2 controls formation of mineralized tissues by inhibition of the Wnt/β-catenin pathway; Sost in dentin and Dkk1 in bone, as previously demonstrated.
-
Isolated Dentinogenesis imperfecta and dentin dysplasia: revision of the classification
European Journal of Human Genetics, 2015Co-Authors: Muriel De La Dure-molla, Benjamin Philippe Fournier, Ariane BerdalAbstract:Dentinogenesis imperfecta is an autosomal dominant disease characterized by severe hypomineralization of dentin and altered dentin structure. Dentin extra cellular matrix is composed of 90% of collagen type I and 10% of non-collagenous proteins among which dentin sialoprotein (DSP), dentin glycoprotein (DGP) and dentin phosphoprotein (DPP) are crucial in Dentinogenesis. These proteins are encoded by a single gene: dentin sialophosphoprotein (DSPP) and undergo several post-translational modifications such as glycosylation and phosphorylation to contribute and to control mineralization. Human mutations of this DSPP gene are responsible for three isolated dentinal diseases classified by Shield in 1973: type II and III Dentinogenesis imperfecta and type II dentin dysplasia. Shield classification was based on clinical phenotypes observed in patient. Genetics results show now that these three diseases are a severity variation of the same pathology. So this review aims to revise and to propose a new classification of the isolated forms of DI to simplify diagnosis for practitioners.
-
regenerative endodontics regeneration or repair
Journal of Endodontics, 2014Co-Authors: Stéphane Simon, Ariane Berdal, Phillip TomsonAbstract:Recent advances in biotechnology and translational research have made it possible to provide treatment modalities that protect the vital pulp, allow manipulation of reactionary and reparative Dentinogenesis, and, more recently, permit revascularization of an infected root canal space. These approaches are referred to as regenerative procedures. The method currently used to determine the origin of the tissue secreted during the repair/regeneration process is largely based on the identification of cellular markers (usually proteins) left by cells that were responsible for this tissue production. The presence of these proteins in conjunction with other indicators of cellular behavior (especially biomineralization) and analysis of the structure of the newly generated tissue allow conclusions to be made of how it was formed. Thus far, it has not been possible to truly establish the biological mechanism controlling tertiary Dentinogenesis. This article considers current therapeutic techniques to treat the dentin-pulp complex and contextualize them in terms of reparative and regenerative processes. Although it may be considered a semantic argument rather than a biological one, the definitions of regeneration and repair are explored to clarify our position in this era of regenerative endodontics.
-
the map kinase pathway is involved in odontoblast stimulation via p38 phosphorylation
Journal of Endodontics, 2010Co-Authors: Stéphane Simon, Philip J. Lumley, Anthony J. Smith, Ariane Berdal, Paul R CooperAbstract:Abstract Introduction We have previously shown that the p38 gene is highly expressed in odontoblasts during active primary Dentinogenesis, but is drastically down-regulated as cells become quiescent in secondary Dentinogenesis. Based on these observations, we hypothesized that p38 expression might be upregulated, and the protein activated by phosphorylation, when odontoblasts are stimulated such as during tertiary reactionary Dentinogenesis. Methods We stimulated immortalized, odontoblast-like MDPC-23 cells, alone or in combination, with heat-inactivated Streptococcus mutans , EDTA-extracted dentine matrix proteins (DMPs), or growth factors, including transforming growth factor (TGF)-β1, tumor necrosis factor-α (TNF-α), and adrenomedullin (ADM). We used ELISA to measure the resulting phosphorylation of the p38 protein, as well as its degree of nuclear translocation. Results Our results suggest that the p38-MAPKinase pathway is activated during odontoblast stimulation in tertiary Dentinogenesis by both p38 phosphorylation and enhanced nuclear translocation. Conclusions Data indicate that odontoblast behaviour therefore potentially recapitulates that during active primary Dentinogenesis.
Stéphane Simon - One of the best experts on this subject based on the ideXlab platform.
-
Sclerostin Deficiency Promotes Reparative Dentinogenesis.
Journal of dental research, 2017Co-Authors: Anne-margaux Collignon, Stéphane Simon, Ariane Berdal, Nawel Amri, Julie Lesieur, Jérémy Sadoine, Sandy Ribes, S. Menashi, Gaël Y. Rochefort, Catherine ChaussainAbstract:In humans, the SOST gene encodes sclerostin, an inhibitor of bone growth and remodeling, which also negatively regulates the bone repair process. Sclerostin has also been implicated in tooth formation, but its potential role in pulp healing remains unknown. The aim of this study was to explore the role of sclerostin in reparative Dentinogenesis using Sost knockout mice ( Sost-/-). The pulps of the first maxillary molars were mechanically exposed in 3-mo-old Sost-/- and wild-type (WT) mice ( n = 14 mice per group), capped with mineral trioxide aggregate cement, and the cavities were filled with a bonded composite resin. Reparative Dentinogenesis was dynamically followed up by micro-computed tomography and characterized by histological analyses. Presurgical analysis revealed a significantly lower pulp volume in Sost-/- mice compared with WT. At 30 and 49 d postsurgery, a large-forming reparative mineralized bridge, associated with osteopontin-positive mineralization foci, was observed in the Sost-/- pulps, whereas a much smaller bridge was detected in WT. At the longer time points, the bridge, which was associated with dentin sialoprotein-positive cells, had expanded in both groups but remained significantly larger in Sost-/- pulps. Sclerostin expression in the healing WT pulps was detected in the cells neighboring the forming dentin bridge. In vitro, mineralization induced by Sost-/- dental pulp cells (DPCs) was also dramatically enhanced when compared with WT DPCs. These observations were associated with an increased Sost expression in WT cells. Taken together, our data show that sclerostin deficiency hastened reparative Dentinogenesis after pulp injury, suggesting that the inhibition of sclerostin may constitute a promising therapeutic strategy for improving the healing of damaged pulps.
-
distorted patterns of Dentinogenesis and eruption in msx2 null mutants involvement of sost sclerostin
American Journal of Pathology, 2016Co-Authors: Nawel Amri, Stéphane Simon, Stephane X Djole, Stephane Petit, Sylvie Babajko, Amelie E Coudert, Beatriz Castaneda, Ariane BerdalAbstract:The muscle segment homeogenes Msx1 and Msx2 play a major role in tooth and bone formation. Periodontal osteoclast impairment also occurs in Msx2 null mutant mice, which is restored by overexpression of the receptor activator of NF-κB targeted in osteoclast lineage. Here, we investigated the role of Msx2 in Dentinogenesis. Experiments were performed on Msx2(-/-) mice and the MDPC-23 odontoblastic cell line. After Msx2 gene silencing, real-time quantitative RT-PCR data showed significant overexpression of Runx2, Bglap, Dspp, and Alpl. Of three inhibitors of Wnt/β-catenin signaling (Dkk1, SostDc1, and Sost/Sclerostin), only Sost was expressed in postnatal teeth and overexpressed in Msx2(-/-) tooth samples. Initial crown dentin formation-primary Dentinogenesis-occurred fairly normally in Msx2(-/-) teeth, albeit with distorted cusp patterns. Later stages of tooth development were characterized by a deviation from secondary toward tertiary Dentinogenesis with osteodentin formation and impaired dentin deposition leading to limited root elongation. In Msx2(-/-)/receptor activator of NF-κB-transgenic double mutants, the dentin phenotype, notably in the roots, was rescued and sclerostin levels were normalized. These data suggest that Msx2 may act indirectly on Dentinogenesis by controlling osteoclast activity and the signaling network related to eruption, supporting and further extending the concept that Msx2 controls formation of mineralized tissues by inhibition of the Wnt/β-catenin pathway; Sost in dentin and Dkk1 in bone, as previously demonstrated.
-
regenerative endodontics regeneration or repair
Journal of Endodontics, 2014Co-Authors: Stéphane Simon, Ariane Berdal, Phillip TomsonAbstract:Recent advances in biotechnology and translational research have made it possible to provide treatment modalities that protect the vital pulp, allow manipulation of reactionary and reparative Dentinogenesis, and, more recently, permit revascularization of an infected root canal space. These approaches are referred to as regenerative procedures. The method currently used to determine the origin of the tissue secreted during the repair/regeneration process is largely based on the identification of cellular markers (usually proteins) left by cells that were responsible for this tissue production. The presence of these proteins in conjunction with other indicators of cellular behavior (especially biomineralization) and analysis of the structure of the newly generated tissue allow conclusions to be made of how it was formed. Thus far, it has not been possible to truly establish the biological mechanism controlling tertiary Dentinogenesis. This article considers current therapeutic techniques to treat the dentin-pulp complex and contextualize them in terms of reparative and regenerative processes. Although it may be considered a semantic argument rather than a biological one, the definitions of regeneration and repair are explored to clarify our position in this era of regenerative endodontics.
-
the map kinase pathway is involved in odontoblast stimulation via p38 phosphorylation
Journal of Endodontics, 2010Co-Authors: Stéphane Simon, Philip J. Lumley, Anthony J. Smith, Ariane Berdal, Paul R CooperAbstract:Abstract Introduction We have previously shown that the p38 gene is highly expressed in odontoblasts during active primary Dentinogenesis, but is drastically down-regulated as cells become quiescent in secondary Dentinogenesis. Based on these observations, we hypothesized that p38 expression might be upregulated, and the protein activated by phosphorylation, when odontoblasts are stimulated such as during tertiary reactionary Dentinogenesis. Methods We stimulated immortalized, odontoblast-like MDPC-23 cells, alone or in combination, with heat-inactivated Streptococcus mutans , EDTA-extracted dentine matrix proteins (DMPs), or growth factors, including transforming growth factor (TGF)-β1, tumor necrosis factor-α (TNF-α), and adrenomedullin (ADM). We used ELISA to measure the resulting phosphorylation of the p38 protein, as well as its degree of nuclear translocation. Results Our results suggest that the p38-MAPKinase pathway is activated during odontoblast stimulation in tertiary Dentinogenesis by both p38 phosphorylation and enhanced nuclear translocation. Conclusions Data indicate that odontoblast behaviour therefore potentially recapitulates that during active primary Dentinogenesis.
Furong Xie - One of the best experts on this subject based on the ideXlab platform.
-
Table_2_Conditional Knockout of Raptor/mTORC1 Results in Dentin Malformation.xlsx
2019Co-Authors: Furong Xie, Qinggang Dai, Xiao Liu, Jun WangAbstract:mTORC1 signaling plays an important role in extracellular and intracellular signals, including growth factors, nutrients, energy metabolism, and stress. However, the functional role of mTORC1 in Dentinogenesis is unknown. To study the role of Raptor/mTORC1 in Dentinogenesis, an Raptorfl/fl; Osx-Cre (Rap-Osx) mouse, in which Raptor was conditionally deleted in odontoblasts and dental mesenchymal cells, was generated, and postnatal tooth development was compared between Rap-Osx mice and control littermates. Rap-Osx mice presented a phenotype known as Dentinogenesis imperfecta and had smaller tooth volume, a thinner dentin layer and a larger pulp chamber. The proliferation and differentiation of odontoblasts/preodontoblasts were attenuated in mutant mice, which was likely responsible for the defects in Dentinogenesis. Raptor/mTORC1-pS6K1 signaling was inactivated during tooth development in Rap-Osx mice, whereas it was activated in control mice. These results indicate that Raptor/mTORC1 plays a critical role in Dentinogenesis via promoting odontoblasts/preodontoblasts proliferation and differentiation. Raptor/mTORC1 might regulate tooth development through the pS6K1 signaling pathway.
-
Image_5_Conditional Knockout of Raptor/mTORC1 Results in Dentin Malformation.jpeg
2019Co-Authors: Furong Xie, Qinggang Dai, Xiao Liu, Jun WangAbstract:mTORC1 signaling plays an important role in extracellular and intracellular signals, including growth factors, nutrients, energy metabolism, and stress. However, the functional role of mTORC1 in Dentinogenesis is unknown. To study the role of Raptor/mTORC1 in Dentinogenesis, an Raptorfl/fl; Osx-Cre (Rap-Osx) mouse, in which Raptor was conditionally deleted in odontoblasts and dental mesenchymal cells, was generated, and postnatal tooth development was compared between Rap-Osx mice and control littermates. Rap-Osx mice presented a phenotype known as Dentinogenesis imperfecta and had smaller tooth volume, a thinner dentin layer and a larger pulp chamber. The proliferation and differentiation of odontoblasts/preodontoblasts were attenuated in mutant mice, which was likely responsible for the defects in Dentinogenesis. Raptor/mTORC1-pS6K1 signaling was inactivated during tooth development in Rap-Osx mice, whereas it was activated in control mice. These results indicate that Raptor/mTORC1 plays a critical role in Dentinogenesis via promoting odontoblasts/preodontoblasts proliferation and differentiation. Raptor/mTORC1 might regulate tooth development through the pS6K1 signaling pathway.
-
Conditional Knockout of Raptor/mTORC1 Results in Dentin Malformation
Frontiers Media S.A., 2019Co-Authors: Furong Xie, Qinggang Dai, Xiao Liu, Jun WangAbstract:mTORC1 signaling plays an important role in extracellular and intracellular signals, including growth factors, nutrients, energy metabolism, and stress. However, the functional role of mTORC1 in Dentinogenesis is unknown. To study the role of Raptor/mTORC1 in Dentinogenesis, an Raptorfl/fl; Osx-Cre (Rap-Osx) mouse, in which Raptor was conditionally deleted in odontoblasts and dental mesenchymal cells, was generated, and postnatal tooth development was compared between Rap-Osx mice and control littermates. Rap-Osx mice presented a phenotype known as Dentinogenesis imperfecta and had smaller tooth volume, a thinner dentin layer and a larger pulp chamber. The proliferation and differentiation of odontoblasts/preodontoblasts were attenuated in mutant mice, which was likely responsible for the defects in Dentinogenesis. Raptor/mTORC1-pS6K1 signaling was inactivated during tooth development in Rap-Osx mice, whereas it was activated in control mice. These results indicate that Raptor/mTORC1 plays a critical role in Dentinogenesis via promoting odontoblasts/preodontoblasts proliferation and differentiation. Raptor/mTORC1 might regulate tooth development through the pS6K1 signaling pathway
Jian Q Feng - One of the best experts on this subject based on the ideXlab platform.
-
Application of Cell Lineage Tracing Combined with Immunofluorescence in the Study of Dentinogenesis.
Methods of Molecular Biology, 2019Co-Authors: Yan Jing, Chaoyuan Li, Jian Q FengAbstract:: The cell lineage tracing system has been used predominantly in developmental biology studies. The Cre recombinase allows for the activation of the reporter in a specific cell line and all progeny. In this protocol, we will introduce how the cell lineage tracing technique can be performed in the investigation of Dentinogenesis by using Gli1-CreERT2; R26RTomato compound mice. Moreover, we combined cell lineage tracing in conjunction with immunofluorescence-to further define cell fate by analyzing the expression of specific cell markers for odontoblasts. This combination not only broadens the application of cell lineage tracing but also simplifies the generation of compound mice. More importantly, the number, location, and differentiation status of parent cell progeny can be displayed simultaneously, providing more information than cell lineage tracing or immunofluorescence alone. In conclusion, the co-application of cell lineage tracing technique and immunofluorescence is a powerful tool for investigating cell biology in the field of Dentinogenesis and tooth development.
-
the specific role of fam20c in Dentinogenesis
Journal of Dental Research, 2015Co-Authors: Xiaofang Wang, Baozhi Yuan, Jian Q Feng, Ying Liu, Jianbo Wang, Louisbruno Ruest, Chunlin QinAbstract:FAM20C is an evolutionarily reserved molecule highly expressed in mineralized tissues. Previously we demonstrated that Sox2-Cre;Fam20Cfl/fl mice, in which Fam20C was ubiquitously inactivated, had dentin and enamel defects as well as hypophosphatemic rickets. We also showed that K14-Cre;Fam20Cfl/fl mice, in which Fam20C was specifically inactivated in the epithelium, had enamel defects but lacked hypophosphatemia and defects in the bone and dentin. These results indicated that the enamel defects in the Sox2-Cre;Fam20Cfl/fl mice were independent of dentin defects and hypophosphatemia. To determine if the dentin defects in the Sox2-Cre;Fam20Cfl/fl mice were associated with the enamel defects and hypophosphatemia, we crossed Fam20Cfl/fl mice with Wnt1-Cre and Osr2-Cre transgenic mice to inactivate Fam20C in the craniofacial mesenchymal cells that form dentin and alveolar bone. The resulting Wnt1-Cre;Fam20Cfl/fl and Osr2-Cre;Fam20Cfl/fl mice showed remarkable dentin and alveolar bone defects, while their ename...
-
the rescue of dentin matrix protein 1 dmp1 deficient tooth defects by the transgenic expression of dentin sialophosphoprotein dspp indicates that dspp is a downstream effector molecule of dmp1 in Dentinogenesis
Journal of Biological Chemistry, 2013Co-Authors: Monica Prasad Gibson, Bruno L Ruest, Baozhi Yuan, Suzhen Wang, Rena N Dsouza, Jian Q Feng, Xiaofang Wang, Yongbo LuAbstract:Dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein (DSPP) are essential for the formation of dentin. Previous in vitro studies have indicated that DMP1 might regulate the expression of DSPP during Dentinogenesis. To examine whether DMP1 controls Dentinogenesis through the regulation of DSPP in vivo, we cross-bred transgenic mice expressing normal DSPP driven by a 3.6-kb rat Col1a1 promoter with Dmp1 KO mice to generate mice expressing the DSPP transgene in the Dmp1 KO genetic background (referred to as “Dmp1 KO/DSPP Tg mice”). We used morphological, histological, and biochemical techniques to characterize the dentin and alveolar bone of Dmp1 KO/DSPP Tg mice compared with Dmp1 KO and wild-type mice. Our analyses showed that the expression of endogenous DSPP was remarkably reduced in the Dmp1 KO mice. Furthermore, the transgenic expression of DSPP rescued the tooth and alveolar bone defects of the Dmp1 KO mice. In addition, our in vitro analyses showed that DMP1 and its 57-kDa C-terminal fragment significantly up-regulated the Dspp promoter activities in a mesenchymal cell line. In contrast, the expression of DMP1 was not altered in the Dspp KO mice. These results provide strong evidence that DSPP is a downstream effector molecule that mediates the roles of DMP1 in Dentinogenesis.
-
role of the nh2 terminal fragment of dentin sialophosphoprotein in Dentinogenesis
European Journal of Oral Sciences, 2013Co-Authors: Monica Prasad Gibson, Jian Q Feng, Xiaofang Wang, Priyam Jani, Qilin Liu, Qinglin Zhu, Ying Liu, Michael L Paine, Malcolm L Snead, Chunlin QinAbstract:Genetic studies have shown that dentin sialophosphoprotein (DSPP) plays an essential role in Dentinogenesis (1–3). For example, the dentin in Dspp knockout mice is hypomineralized and the predentin is widened, creating a phenotype similar to that of Dentinogenesis imperfecta type III in humans (3). While studies have demonstrated the critical role of DSPP in dentin formation, the mechanism(s) by which DSPP function(s) in biomineralization remain largely unclear. DSPP, first identified by cDNA cloning (4), is a large protein that undergoes proteolytic processing to form the NH2-terminal fragment known as dentin sialoprotein (DSP), proteoglycan form of the NH2-terminal fragment referred to as DSP-PG and a COOH-terminal fragment named dentin phosphoprotein (DPP) (5–7). The sequence of the NH2-terminal fragment (DSP or DSP-PG) lies in the 5′-portion, while the DPP sequence is located in the 3′-region of the DSPP transcript (4, 8–10). Studies done in our laboratory and others established the presence of a proteoglycan form of DSP (known as DSP-PG) (5–7). DSP/DSP-PG and DPP are abundant in the dentin extracellular matrix (ECM) whereas the protein representing the entire sequence (DSPP) is scarcely present, which led to the belief that the processed fragments may be the functional forms of DSPP. Recent work in our laboratory has shown that blocking the proteolytic fragmentation of DSPP inactivates the function(s) of this molecule during Dentinogenesis (11). This observation provides strong evidence that the proteolytic processing of DSPP is an activation event which releases the functional fragments that exert distinct molecular role(s) during dentin formation (11). DPP, discovered in 1967, is the most abundant non collagenous protein (NCP) in the dentin ECM (12, 13). The unusual feature of DPP is the presence of large amounts of aspartic acid (Asp) and phosphoserine (Pse), mostly found in the repeating sequences of (Asp-Pse-Pse)n and (Asp-Pse)n (14,15). Several in vitro mineralization studies have indicated that DPP is an important initiator and modulator for the formation and growth of hydroxyapatite (HA) crystals (16–18). It is believed that the DPP secreted by the odontoblasts is transported to the mineralization front where it binds to collagen fibrils promoting the formation of initial HA. As this mineralization process proceeds, and more predentin is converted to dentin, these mineral crystals grow in an oriented fashion under the modulation of DPP and other non-collagenous proteins (NCPs) that bind to the growing HA faces (19, 20). DSP, discovered in 1981, is much less abundant than DPP in dentin ECM (21). DSP [protein without the glycosaminoglycan (GAG) chains]does not have a significant effect on the in vitro mineral formation and growth (22). Since there is no in vivo data concerning the role of DSP in Dentinogenesis, the functions of this fragment is presently undefined. The recently discovered proteoglycan form of DSP (DSP-PG) is a major component in the proteoglycan pool of the dentin extracellular matrix (ECM) and appears to be more abundant than DSP (5, 6). We believe that the NH2-terminal fragment of DSPP (DSP/DSP-PG) must play a role in biomineralization, distinct from that of the COOH-terminal fragment of DSPP (DPP). DSP-PG from the NH2-terminal sequence of DSPP was found in the dentin ECM at higher amounts than the core protein DSP, which led us to believe that DSP-PG may be the functional form of the NH2-terminal fragment. We hypothesize that the role of DSP-PG may be to prevent the predentin from being mineralized too rapidly and to serve as an antagonist of DPP in Dentinogenesis. In order to examine the function of the NH2-terminal fragment of DSPP in Dentinogenesis, we expressed the NH2-terminal fragment of DSPP in the Dspp-null background (referred as “Dspp KO/DSP Tg”) to analyze the in vivo effects of this fragment in a gain of function experimental approach. In this study, we systematically characterized the dentin of Dspp KO/DSP Tg mice and compared it to the dentin from Dspp-null (Dspp knockout or Dspp KO) mice and wild type (WT) mice. We observed that the dentin of the Dspp KO/DSP Tg mice appeared much worse compared to the Dspp-null mice. The results from this investigation support our hypothesis that the NH2-terminal fragment of DSPP has an inhibitory role in Dentinogenesis.
-
deletion of dentin matrix protein 1 leads to a partial failure of maturation of predentin into dentin hypomineralization and expanded cavities of pulp and root canal during postnatal tooth development
Journal of Biological Chemistry, 2004Co-Authors: Ling Ye, Yongbo Lu, Mary Macdougall, Shubin Zhang, Jianghong Zhang, Zubing Li, Yuji Mishina, Jian Q FengAbstract:Abstract The dentin matrix protein-1 (DMP-1) gene is identified in odontoblasts during both embryonic and postnatal development. In vitro study suggests that this noncollagen acidic phosphoprotein plays a role in mineralization. However, deletion of the Dmp-1 gene has little effect on tooth development during embryogenesis. To address the role of DMP-1 in tooth during postnatal development, we analyzed changes of Dentinogenesis in Dmp-1 null mice from 3 days after birth to 1 year. Here we show that Dmp-1 null mice postnatally develop a profound tooth phenotype characterized by a partial failure of maturation of predentin into dentin, enlarged pulp chambers, increased width of predentin zone with reduced dentin wall, and hypomineralization. The tooth phenotype of these mice is strikingly similar to that in dentin sialophosphoprotein (Dspp) null mice and shares some features of the human disease Dentinogenesis imperfecta III. We have also demonstrated that DSPP levels are reduced in Dmp-1 null mice, suggesting that DSPP is probably regulated by DMP-1 during Dentinogenesis. Finally, we show the absence or delayed development of the third molar in Dmp-1 null mice, which is probably secondary to defects in Dmp-1 null bone. Taken together, these studies suggest that DMP-1 is essential for later Dentinogenesis during postnatal development.
Paul T Sharpe - One of the best experts on this subject based on the ideXlab platform.
-
gsk3 inhibitor induced Dentinogenesis using a hydrogel
Journal of Dental Research, 2021Co-Authors: Lucia K Zaugg, A Alaohali, Christoph Salzlechner, F Suzano, Ana Martinez, Eileen Gentleman, Paul T SharpeAbstract:Small-molecule drugs targeting glycogen synthase kinase 3 (GSK3) as inhibitors of the protein kinase activity are able to stimulate reparative dentine formation. To develop this approach into a viable clinical treatment for exposed pulp lesions, we synthesized a novel, small-molecule noncompetitive adenosine triphosphate (ATP) drug that can be incorporated into a biodegradable hydrogel for placement by syringe into the tooth. This new drug, named NP928, belongs to the thiadiazolidinone (TDZD) family and has equivalent activity to similar drugs of this family such as tideglusib. However, NP928 is more water soluble than other TDZD drugs, making it more suitable for direct delivery into pulp lesions. We have previously reported that biodegradable marine collagen sponges can successfully deliver TDZD drugs to pulp lesions, but this involves in-theater preparation of the material, which is not ideal in a clinical context. To improve surgical handling and delivery, here we incorporated NP928 into a specifically tailored hydrogel that can be placed by syringe into a damaged tooth. This hydrogel is based on biodegradable hyaluronic acid and can be gelled in situ upon dental blue light exposure, similarly to other common dental materials. NP928 released from hyaluronic acid-based hydrogels upregulated Wnt/β-catenin activity in pulp stem cells and fostered reparative dentine formation compared to marine collagen sponges delivering equivalent concentrations of NP928. This drug-hydrogel combination has the potential to be rapidly developed into a therapeutic procedure that is amenable to general dental practice.
-
a mouse model to study reparative Dentinogenesis
Methods of Molecular Biology, 2019Co-Authors: Rebecca Babb, Dhivya Chandrasekaran, Lucia K Zaugg, Paul T SharpeAbstract:Different animal models have been introduced recently to study the process of reparative Dentinogenesis in response to injury-induced pulp exposure. Using a mouse model is advantageous over other animal models since mice can be genetically manipulated to examine specific cellular pathways and lineage trace the progeny of a single cell. However, enabling a standardized molar damage in mice is demanding due to the small size of the teeth compared to the available dental instruments. Here we describe a reproducible and reliable in vivo model that allows us to study Dentinogenesis in the first maxillary mouse molar.
-
axin2 expressing cells differentiate into reparative odontoblasts via autocrine wnt β catenin signaling in response to tooth damage
Scientific Reports, 2017Co-Authors: Rebecca Babb, Dhivya Chandrasekaran, Vitor De Carvalho Moreno Das Neves, Paul T SharpeAbstract:In non-growing teeth, such as mouse and human molars, primary odontoblasts are long-lived post-mitotic cells that secrete dentine throughout the life of the tooth. New odontoblast-like cells are only produced in response to a damage or trauma. Little is known about the molecular events that initiate mesenchymal stem cells to proliferate and differentiate into odontoblast-like cells in response to dentine damage. The reparative and regenerative capacity of multiple mammalian tissues depends on the activation of Wnt/β-catenin signaling pathway. In this study, we investigated the molecular role of Wnt/β-catenin signaling pathway in reparative Dentinogenesis using an in vivo mouse tooth damage model. We found that Axin2 is rapidly upregulated in response to tooth damage and that these Axin2-expressing cells differentiate into new odontoblast-like cells that secrete reparative dentine. In addition, the Axin2-expressing cells produce a source of Wnt that acts in an autocrine manner to modulate reparative Dentinogenesis.