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Brian L Foster - One of the best experts on this subject based on the ideXlab platform.

  • Basic fibroblast growth factor regulates phosphate/pyrophosphate regulatory genes in stem cells isolated from human exfoliated deciduous teeth
    Stem Cell Research & Therapy, 2018
    Co-Authors: Nunthawa Nowwarote, Brian L Foster, Waleerat Sukarawan, Prasit Pavasant, Thanaphum Osathanon
    Abstract:

    Background Basic fibroblast growth factor (bFGF) regulates maintenance of stemness and modulation of osteo/odontogenic differentiation and mineralization in stem cells from human exfoliated deciduous teeth (SHEDs). Mineralization in the bones and teeth is in part controlled by pericellular levels of inorganic phosphate (P_i), a component of hydroxyapatite, and inorganic pyrophosphate (PP_i), an inhibitor of mineralization. The progressive ankylosis protein (gene ANKH ; protein ANKH) and ectonucleotide pyrophosphatase phosphodiesterase 1 ( ENPP1 /ENPP1) increase PP_i and inhibit mineralization, while tissue-nonspecific alkaline phosphatase ( ALPL ; TNAP) is a critical pro-mineralization enzyme that hydrolyzes PP_i. We hypothesized that regulation by bFGF of mineralization in SHEDs occurs by modulation of P_i/PP_i-associated genes. Methods Cells were isolated from human exfoliated deciduous teeth and characterized for mesenchymal stem cell characteristics. Cells were treated with bFGF, and the osteogenic differentiation ability was determined. The mRNA expression was evaluated using real-time polymerase chain reaction. The mineralization was examined using alizarin red S staining. Results Cells isolated from primary teeth expressed mesenchymal stem cell markers, CD44, CD90, and CD105, and were able to differentiate into osteo/odontogenic and adipogenic lineages. Addition of 10 ng/ml bFGF to SHEDs during in vitro osteo/odontogenic differentiation decreased ALPL mRNA expression and ALP enzyme activity, increased ANKH mRNA, and decreased both P_i/PP_i ratio and mineral deposition. Effects of bFGF on ALPL and ANKH expression were detected within 24 h. Addition of 20 mM fibroblast growth factor receptor (FGFR) inhibitor SU5402 revealed the necessity of FGFR-mediated signaling, and inclusion of 1 μg/ml cyclohexamide (CHX) implicated the necessity of protein synthesis for effects on ALPL and ANKH . Addition of exogenous 10 μm PP_i inhibited mineralization and increased ANKH , collagen type 1a1 ( COL1A1 ), and osteopontin ( SPP1 ) mRNA, while addition of exogenous P_i increased mineralization and osterix ( OSX ), ANKH , SPP1 , and dentin matrix protein 1 ( DMP1 ) mRNA. The effects of PP_i and P_i on mineralization could be replicated by short-term 3- and 7-day treatments, suggesting signaling effects in addition to physicochemical regulation of mineral deposition. Conclusion This study reveals for the first time the effects of bFGF on P_i/PP_i regulators in SHEDs and implicates these factors in how bFGF directs osteo/odontogenic differentiation and mineralization by these cells.

  • conditional ALPL ablation phenocopies dental defects of hypophosphatasia
    Journal of Dental Research, 2017
    Co-Authors: Brian L Foster, Sonoko Narisawa, Manisha C Yadav, Martha J Somerman, Esther Cory, Robert L Sah, Pia Kuss, T N Kolli, L Lukashova, Jose Luis Millan
    Abstract:

    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.

  • Central Role of Pyrophosphate in Acellular Cementum Formation
    2016
    Co-Authors: Brian L Foster, Francisco H.umberto Nociti, Kanako J Nagatomo, Sonoko Narisawa, Hanson Fong, Daisy Dunn, Anne B. Tran, Wei Wang, Jose Luis Millán, Martha J Somerman
    Abstract:

    Background: Inorganic pyrophosphate (PPi) is a physiologic inhibitor of hydroxyapatite mineral precipitation involved in regulating mineralized tissue development and pathologic calcification. Local levels of PPi are controlled by antagonistic functions of factors that decrease PPi and promote mineralization (tissue-nonspecific alkaline phosphatase, ALPL/TNAP), and those that increase local PPi and restrict mineralization (progressive ankylosis protein, ANK; ectonucleotide pyrophosphatase phosphodiesterase-1, NPP1). The cementum enveloping the tooth root is essential for tooth function by providing attachment to the surrounding bone via the nonmineralized periodontal ligament. At present, the developmental regulation of cementum remains poorly understood, hampering efforts for regeneration. To elucidate the role of PPi in cementum formation, we analyzed root development in knock-out ( 2/2) mice featuring PPi dysregulation. Results: Excess PPi in the ALPL 2/2 mouse inhibited cementum formation, causing root detachment consistent with premature tooth loss in the human condition hypophosphatasia, though cementoblast phenotype was unperturbed. Deficient PPi in both Ank and Enpp1 2/2 mice significantly increased cementum apposition and overall thickness more tha

  • improvement of the skeletal and dental hypophosphatasia phenotype in ALPL mice by administration of soluble non targeted chimeric alkaline phosphatase
    Bone, 2015
    Co-Authors: Kellen Cristina Da Silva Gasque, Nan E Hatch, Jin Liu, Brian L Foster, Manisha C Yadav, Martha J Somerman, Pia Kuss, Tina Kiffermoreira, Andrea Van Elsas, Jose Luis Millan
    Abstract:

    Abstract Hypophosphatasia (HPP) results from ALPL gene mutations, which lead to a deficiency of tissue-nonspecific alkaline phosphatase (TNAP), and accumulation of inorganic pyrophosphate, a potent inhibitor of mineralization that is also a natural substrate of TNAP, in the extracellular space. HPP causes mineralization disorders including soft bones (rickets or osteomalacia) and defects in teeth and periodontal tissues. Enzyme replacement therapy using mineral-targeting recombinant TNAP has proven effective in preventing skeletal and dental defects in TNAP knockout ( ALPL −/− ) mice, a model for life-threatening HPP. Here, we show that the administration of a soluble, intestinal-like chimeric alkaline phosphatase (ChimAP) improves the manifestations of HPP in ALPL −/− mice. Mice received daily subcutaneous injections of ChimAP at doses of 1, 8 or 16 mg/kg, from birth for up to 53 days. Lifespan and body weight of ALPL −/− mice were normalized, and vitamin B6-associated seizures were absent with 16 mg/kg/day of ChimAP. Radiographs, μCT and histological analyses documented improved mineralization in cortical and trabecular bone and secondary ossification centers in long bones of ChimAP16-treated mice. There was no evidence of craniosynostosis in the ChimAP16-treated mice and we did not detect ectopic calcification by radiography and histology in the aortas, stomachs, kidneys or lungs in any of the treatment groups. Molar tooth development and function improved with the highest ChimAP dose, including enamel, dentin, and tooth morphology. Cementum remained deficient and alveolar bone mineralization was reduced compared to controls, though ChimAP-treated ALPL −/− mice featured periodontal attachment and retained teeth. This study provides the first evidence for the pharmacological efficacy of ChimAP for use in the treatment of skeletal and dental manifestations of HPP.

  • tooth root dentin mineralization defects in a mouse model of hypophosphatasia
    Journal of Bone and Mineral Research, 2013
    Co-Authors: Brian L Foster, Francisco H.umberto Nociti, Jose Luis Millan, Kanako J Nagatomo, A B Tran, Sonoko Narisawa, Manisha C Yadav, Martha J Somerman
    Abstract:

    Tissue-nonspecific alkaline phosphatase (TNAP) is expressed in mineralizing tissues and functions to reduce pyrophosphate (PPi), a potent inhibitor of mineralization. Loss of TNAP function causes hypophosphatasia (HPP), a heritable disorder marked by increased PPi, resulting in rickets and osteomalacia. Tooth root cementum defects are well described in both HPP patients and in ALPL−/− mice, a model for infantile HPP. In ALPL−/− mice, dentin mineralization is specifically delayed in the root; however, reports from human HPP patients are variable and inconsistent regarding dentin defects. In the current study, we aimed to define the molecular basis for changes in dentinogenesis observed in ALPL−/− mice. TNAP was found to be highly expressed by mature odontoblasts, and ALPL−/− molar and incisor roots featured defective dentin mineralization, ranging from a mild delay to severely disturbed root dentinogenesis. Lack of mantle dentin mineralization was associated with disordered and dysmorphic odontoblasts having disrupted expression of marker genes osteocalcin and dentin sialophosphoprotein. The formation of, initiation of mineralization within, and rupture of matrix vesicles in ALPL−/− dentin matrix was not affected. Osteopontin (OPN), an inhibitor of mineralization that contributes to the skeletal pathology in ALPL−/− mice, was present in the generally unmineralized ALPL−/− mantle dentin at ruptured mineralizing matrix vesicles, as detected by immunohistochemistry and by immunogold labeling. However, ablating the OPN-encoding Spp1 gene in ALPL−/− mice was insufficient to rescue the dentin mineralization defect. Administration of bioengineered mineral-targeting human TNAP (ENB-0040) to ALPL−/− mice corrected defective dentin mineralization in the molar roots. These studies reveal that TNAP participates in root dentin formation and confirm that reduction of PPi during dentinogenesis is necessary for odontoblast differentiation, dentin matrix secretion, and mineralization. Furthermore, these results elucidate developmental mechanisms underlying dentin pathology in HPP patients, and begin to explain the reported variability in the dentin/pulp complex pathology in these patients. © 2013 American Society for Bone and Mineral Research

Martha J Somerman - One of the best experts on this subject based on the ideXlab platform.

  • conditional ALPL ablation phenocopies dental defects of hypophosphatasia
    Journal of Dental Research, 2017
    Co-Authors: Brian L Foster, Sonoko Narisawa, Manisha C Yadav, Martha J Somerman, Esther Cory, Robert L Sah, Pia Kuss, T N Kolli, L Lukashova, Jose Luis Millan
    Abstract:

    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.

  • Central Role of Pyrophosphate in Acellular Cementum Formation
    2016
    Co-Authors: Brian L Foster, Francisco H.umberto Nociti, Kanako J Nagatomo, Sonoko Narisawa, Hanson Fong, Daisy Dunn, Anne B. Tran, Wei Wang, Jose Luis Millán, Martha J Somerman
    Abstract:

    Background: Inorganic pyrophosphate (PPi) is a physiologic inhibitor of hydroxyapatite mineral precipitation involved in regulating mineralized tissue development and pathologic calcification. Local levels of PPi are controlled by antagonistic functions of factors that decrease PPi and promote mineralization (tissue-nonspecific alkaline phosphatase, ALPL/TNAP), and those that increase local PPi and restrict mineralization (progressive ankylosis protein, ANK; ectonucleotide pyrophosphatase phosphodiesterase-1, NPP1). The cementum enveloping the tooth root is essential for tooth function by providing attachment to the surrounding bone via the nonmineralized periodontal ligament. At present, the developmental regulation of cementum remains poorly understood, hampering efforts for regeneration. To elucidate the role of PPi in cementum formation, we analyzed root development in knock-out ( 2/2) mice featuring PPi dysregulation. Results: Excess PPi in the ALPL 2/2 mouse inhibited cementum formation, causing root detachment consistent with premature tooth loss in the human condition hypophosphatasia, though cementoblast phenotype was unperturbed. Deficient PPi in both Ank and Enpp1 2/2 mice significantly increased cementum apposition and overall thickness more tha

  • improvement of the skeletal and dental hypophosphatasia phenotype in ALPL mice by administration of soluble non targeted chimeric alkaline phosphatase
    Bone, 2015
    Co-Authors: Kellen Cristina Da Silva Gasque, Nan E Hatch, Jin Liu, Brian L Foster, Manisha C Yadav, Martha J Somerman, Pia Kuss, Tina Kiffermoreira, Andrea Van Elsas, Jose Luis Millan
    Abstract:

    Abstract Hypophosphatasia (HPP) results from ALPL gene mutations, which lead to a deficiency of tissue-nonspecific alkaline phosphatase (TNAP), and accumulation of inorganic pyrophosphate, a potent inhibitor of mineralization that is also a natural substrate of TNAP, in the extracellular space. HPP causes mineralization disorders including soft bones (rickets or osteomalacia) and defects in teeth and periodontal tissues. Enzyme replacement therapy using mineral-targeting recombinant TNAP has proven effective in preventing skeletal and dental defects in TNAP knockout ( ALPL −/− ) mice, a model for life-threatening HPP. Here, we show that the administration of a soluble, intestinal-like chimeric alkaline phosphatase (ChimAP) improves the manifestations of HPP in ALPL −/− mice. Mice received daily subcutaneous injections of ChimAP at doses of 1, 8 or 16 mg/kg, from birth for up to 53 days. Lifespan and body weight of ALPL −/− mice were normalized, and vitamin B6-associated seizures were absent with 16 mg/kg/day of ChimAP. Radiographs, μCT and histological analyses documented improved mineralization in cortical and trabecular bone and secondary ossification centers in long bones of ChimAP16-treated mice. There was no evidence of craniosynostosis in the ChimAP16-treated mice and we did not detect ectopic calcification by radiography and histology in the aortas, stomachs, kidneys or lungs in any of the treatment groups. Molar tooth development and function improved with the highest ChimAP dose, including enamel, dentin, and tooth morphology. Cementum remained deficient and alveolar bone mineralization was reduced compared to controls, though ChimAP-treated ALPL −/− mice featured periodontal attachment and retained teeth. This study provides the first evidence for the pharmacological efficacy of ChimAP for use in the treatment of skeletal and dental manifestations of HPP.

  • tooth root dentin mineralization defects in a mouse model of hypophosphatasia
    Journal of Bone and Mineral Research, 2013
    Co-Authors: Brian L Foster, Francisco H.umberto Nociti, Jose Luis Millan, Kanako J Nagatomo, A B Tran, Sonoko Narisawa, Manisha C Yadav, Martha J Somerman
    Abstract:

    Tissue-nonspecific alkaline phosphatase (TNAP) is expressed in mineralizing tissues and functions to reduce pyrophosphate (PPi), a potent inhibitor of mineralization. Loss of TNAP function causes hypophosphatasia (HPP), a heritable disorder marked by increased PPi, resulting in rickets and osteomalacia. Tooth root cementum defects are well described in both HPP patients and in ALPL−/− mice, a model for infantile HPP. In ALPL−/− mice, dentin mineralization is specifically delayed in the root; however, reports from human HPP patients are variable and inconsistent regarding dentin defects. In the current study, we aimed to define the molecular basis for changes in dentinogenesis observed in ALPL−/− mice. TNAP was found to be highly expressed by mature odontoblasts, and ALPL−/− molar and incisor roots featured defective dentin mineralization, ranging from a mild delay to severely disturbed root dentinogenesis. Lack of mantle dentin mineralization was associated with disordered and dysmorphic odontoblasts having disrupted expression of marker genes osteocalcin and dentin sialophosphoprotein. The formation of, initiation of mineralization within, and rupture of matrix vesicles in ALPL−/− dentin matrix was not affected. Osteopontin (OPN), an inhibitor of mineralization that contributes to the skeletal pathology in ALPL−/− mice, was present in the generally unmineralized ALPL−/− mantle dentin at ruptured mineralizing matrix vesicles, as detected by immunohistochemistry and by immunogold labeling. However, ablating the OPN-encoding Spp1 gene in ALPL−/− mice was insufficient to rescue the dentin mineralization defect. Administration of bioengineered mineral-targeting human TNAP (ENB-0040) to ALPL−/− mice corrected defective dentin mineralization in the molar roots. These studies reveal that TNAP participates in root dentin formation and confirm that reduction of PPi during dentinogenesis is necessary for odontoblast differentiation, dentin matrix secretion, and mineralization. Furthermore, these results elucidate developmental mechanisms underlying dentin pathology in HPP patients, and begin to explain the reported variability in the dentin/pulp complex pathology in these patients. © 2013 American Society for Bone and Mineral Research

  • tooth root dentin mineralization defects in a mouse model of hypophosphatasia
    Journal of Bone and Mineral Research, 2013
    Co-Authors: Brian L Foster, Francisco H.umberto Nociti, Jose Luis Millan, Kanako J Nagatomo, A B Tran, Sonoko Narisawa, Manisha C Yadav, H W Tso, Martha J Somerman
    Abstract:

    Tissue-nonspecific alkaline phosphatase (TNAP) is expressed in mineralizing tissues and functions to reduce pyrophosphate (PP(i) ), a potent inhibitor of mineralization. Loss of TNAP function causes hypophosphatasia (HPP), a heritable disorder marked by increased PP(i) , resulting in rickets and osteomalacia. Tooth root cementum defects are well described in both HPP patients and in ALPL(-/-) mice, a model for infantile HPP. In ALPL(-/-) mice, dentin mineralization is specifically delayed in the root; however, reports from human HPP patients are variable and inconsistent regarding dentin defects. In the current study, we aimed to define the molecular basis for changes in dentinogenesis observed in ALPL(-/-) mice. TNAP was found to be highly expressed by mature odontoblasts, and ALPL(-/-) molar and incisor roots featured defective dentin mineralization, ranging from a mild delay to severely disturbed root dentinogenesis. Lack of mantle dentin mineralization was associated with disordered and dysmorphic odontoblasts having disrupted expression of marker genes osteocalcin and dentin sialophosphoprotein. The formation of, initiation of mineralization within, and rupture of matrix vesicles in ALPL(-/-) dentin matrix was not affected. Osteopontin (OPN), an inhibitor of mineralization that contributes to the skeletal pathology in ALPL(-/-) mice, was present in the generally unmineralized ALPL(-/-) mantle dentin at ruptured mineralizing matrix vesicles, as detected by immunohistochemistry and by immunogold labeling. However, ablating the OPN-encoding Spp1 gene in ALPL(-/-) mice was insufficient to rescue the dentin mineralization defect. Administration of bioengineered mineral-targeting human TNAP (ENB-0040) to ALPL(-/-) mice corrected defective dentin mineralization in the molar roots. These studies reveal that TNAP participates in root dentin formation and confirm that reduction of PP(i) during dentinogenesis is necessary for odontoblast differentiation, dentin matrix secretion, and mineralization. Furthermore, these results elucidate developmental mechanisms underlying dentin pathology in HPP patients, and begin to explain the reported variability in the dentin/pulp complex pathology in these patients.

Jose Luis Millan - One of the best experts on this subject based on the ideXlab platform.

  • dental defects in the primary dentition associated with hypophosphatasia from biallelic ALPL mutations
    Bone, 2021
    Co-Authors: K Kramer, M B Chavez, Jose Luis Millan, T N Kolli, A T Tran, F Farah, Michelle H Tan, E Lira Dos J Santos, H F Wimer, Larry J Suva
    Abstract:

    ALPL encodes tissue-nonspecific alkaline phosphatase (TNAP), an enzyme expressed in bone, teeth, liver, and kidney. ALPL loss-of-function mutations cause hypophosphatasia (HPP), an inborn error-of-metabolism that produces skeletal and dental mineralization defects. Case reports describe widely varying dental phenotypes, making it unclear how HPP comparatively affects the three unique dental mineralized tissues: enamel, dentin, and cementum. We hypothesized that HPP affected all dental mineralized tissues and aimed to establish quantitative measurements of dental tissues in a subject with HPP. The female proband was diagnosed with HPP during childhood based on reduced alkaline phosphatase activity (ALP), mild rachitic skeletal effects, and premature primary tooth loss. The diagnosis was subsequently confirmed genetically by the presence of compound heterozygous ALPL mutations (exon 5: c.346G>A, p.A116T; exon 10: c.1077C>G, p.I359M). Dental defects in 8 prematurely exfoliated primary teeth were analyzed by high resolution micro-computed tomography (micro-CT) and histology. Similarities to the ALPL-/- mouse model of HPP were identified by additional analyses of murine dentoalveolar tissues. Primary teeth from the proband exhibited substantial remaining root structure compared to healthy control teeth. Enamel and dentin densities were not adversely affected in HPP vs. control teeth. However, analysis of discrete dentin regions revealed an approximate 10% reduction in the density of outer mantle dentin of HPP vs. control teeth. All 4 incisors and the molar lacked acellular cementum by micro-CT and histology, but surprisingly, 2 of 3 prematurely exfoliated canines exhibited apparently normal acellular cementum. Based on dentin findings in the proband's teeth, we examined dentoalveolar tissues in a mouse model of HPP, revealing that the delayed initiation of mineralization in the incisor mantle dentin was associated with a broader lack of circumpulpal dentin mineralization. This study describes a quantitative approach to measure effects of HPP on dental tissues. This approach has uncovered a previously unrecognized novel mantle dentin defect in HPP, as well as a surprising and variable cementum phenotype within the teeth from the same HPP subject.

  • inhibition of tissue nonspecific alkaline phosphatase attenuates ectopic mineralization in the abcc6 mouse model of pxe but not in the enpp1 mutant mouse models of gaci
    Journal of Investigative Dermatology, 2019
    Co-Authors: J Huang, Jose Luis Millan, Anthony B Pinkerton, Bertrand D Van Zelst, Michael A Levine, John P Sundberg, Jouni Uitto
    Abstract:

    Pseudoxanthoma elasticum (PXE), a prototype of heritable ectopic mineralization disorders, is caused by mutations in the ABCC6 gene encoding a putative efflux transporter ABCC6. It was recently shown that the absence of ABCC6-mediated adenosine triphosphate release from the liver and, consequently, reduced inorganic pyrophosphate levels underlie the pathogenesis of PXE. Given that tissue-nonspecific alkaline phosphatase (TNAP), encoded by ALPL, is the enzyme responsible for degrading inorganic pyrophosphate, we hypothesized that reducing TNAP levels either by genetic or pharmacological means would lead to amelioration of the ectopic mineralization phenotype in the Abcc6–/– mouse model of PXE. Thus, we bred Abcc6–/– mice to heterozygous ALPL+/– mice that display approximately 50% plasma TNAP activity. The Abcc6–/–ALPL+/– double-mutant mice showed 52% reduction of mineralization in the muzzle skin compared with the Abcc6–/–ALPL+/+ mice. Subsequently, oral administration of SBI-425, a small molecule inhibitor of TNAP, resulted in 61% reduction of plasma TNAP activity and 58% reduction of mineralization in the muzzle skin of Abcc6–/– mice. By contrast, SBI-425 treatment of Enpp1 mutant mice, another model of ectopic mineralization associated with reduced inorganic pyrophosphate, failed to reduce muzzle skin mineralization. These results suggest that inhibition of TNAP might provide a promising treatment strategy for PXE, a currently intractable disease.

  • conditional ALPL ablation phenocopies dental defects of hypophosphatasia
    Journal of Dental Research, 2017
    Co-Authors: Brian L Foster, Sonoko Narisawa, Manisha C Yadav, Martha J Somerman, Esther Cory, Robert L Sah, Pia Kuss, T N Kolli, L Lukashova, Jose Luis Millan
    Abstract:

    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.

  • enzyme replacement for craniofacial skeletal defects and craniosynostosis in murine hypophosphatasia
    Bone, 2015
    Co-Authors: Jin Liu, Hwa Kyung Nam, Cassie Campbell, Jose Luis Millan, Manisha C Yadav, Alexandre Caron, Nan E Hatch
    Abstract:

    Hypophosphatasia (HPP) is an inborn-error-of-metabolism disorder characterized by deficient bone and tooth mineralization due to loss-of function mutations in the gene (ALPL) encoding tissue-nonspecific alkaline phosphatase (TNAP). ALPL(-/-) mice exhibit many characteristics seen in infantile HPP including long bone and tooth defects, vitamin B6 responsive seizures and craniosynostosis. Previous reports demonstrated that a mineral-targeted form of TNAP rescues long bone, vertebral and tooth mineralization defects in ALPL(-/-) mice. Here we report that enzyme replacement with mineral-targeted TNAP (asfotase-alfa) also prevents craniosynostosis (the premature fusion of cranial bones) and additional craniofacial skeletal abnormalities in ALPL(-/-) mice. Craniosynostosis, cranial bone volume and density, and craniofacial shape abnormalities were assessed by microscopy, histology, digital caliper measurements and micro CT. We found that craniofacial shape defects, cranial bone mineralization and craniosynostosis were corrected in ALPL(-/-) mice injected daily subcutaneously starting at birth with recombinant enzyme. Analysis of ALPL(-/-) calvarial cells indicates that TNAP deficiency leads to aberrant osteoblastic gene expression and diminished proliferation. Some but not all of these cellular abnormalities were rescued by treatment with inorganic phosphate. These results confirm an essential role for TNAP in craniofacial skeletal development and demonstrate the efficacy of early postnatal mineral-targeted enzyme replacement for preventing craniofacial abnormalities including craniosynostosis in murine infantile HPP.

  • improvement of the skeletal and dental hypophosphatasia phenotype in ALPL mice by administration of soluble non targeted chimeric alkaline phosphatase
    Bone, 2015
    Co-Authors: Kellen Cristina Da Silva Gasque, Nan E Hatch, Jin Liu, Brian L Foster, Manisha C Yadav, Martha J Somerman, Pia Kuss, Tina Kiffermoreira, Andrea Van Elsas, Jose Luis Millan
    Abstract:

    Abstract Hypophosphatasia (HPP) results from ALPL gene mutations, which lead to a deficiency of tissue-nonspecific alkaline phosphatase (TNAP), and accumulation of inorganic pyrophosphate, a potent inhibitor of mineralization that is also a natural substrate of TNAP, in the extracellular space. HPP causes mineralization disorders including soft bones (rickets or osteomalacia) and defects in teeth and periodontal tissues. Enzyme replacement therapy using mineral-targeting recombinant TNAP has proven effective in preventing skeletal and dental defects in TNAP knockout ( ALPL −/− ) mice, a model for life-threatening HPP. Here, we show that the administration of a soluble, intestinal-like chimeric alkaline phosphatase (ChimAP) improves the manifestations of HPP in ALPL −/− mice. Mice received daily subcutaneous injections of ChimAP at doses of 1, 8 or 16 mg/kg, from birth for up to 53 days. Lifespan and body weight of ALPL −/− mice were normalized, and vitamin B6-associated seizures were absent with 16 mg/kg/day of ChimAP. Radiographs, μCT and histological analyses documented improved mineralization in cortical and trabecular bone and secondary ossification centers in long bones of ChimAP16-treated mice. There was no evidence of craniosynostosis in the ChimAP16-treated mice and we did not detect ectopic calcification by radiography and histology in the aortas, stomachs, kidneys or lungs in any of the treatment groups. Molar tooth development and function improved with the highest ChimAP dose, including enamel, dentin, and tooth morphology. Cementum remained deficient and alveolar bone mineralization was reduced compared to controls, though ChimAP-treated ALPL −/− mice featured periodontal attachment and retained teeth. This study provides the first evidence for the pharmacological efficacy of ChimAP for use in the treatment of skeletal and dental manifestations of HPP.

Sonoko Narisawa - One of the best experts on this subject based on the ideXlab platform.

  • conditional ALPL ablation phenocopies dental defects of hypophosphatasia
    Journal of Dental Research, 2017
    Co-Authors: Brian L Foster, Sonoko Narisawa, Manisha C Yadav, Martha J Somerman, Esther Cory, Robert L Sah, Pia Kuss, T N Kolli, L Lukashova, Jose Luis Millan
    Abstract:

    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.

  • Central Role of Pyrophosphate in Acellular Cementum Formation
    2016
    Co-Authors: Brian L Foster, Francisco H.umberto Nociti, Kanako J Nagatomo, Sonoko Narisawa, Hanson Fong, Daisy Dunn, Anne B. Tran, Wei Wang, Jose Luis Millán, Martha J Somerman
    Abstract:

    Background: Inorganic pyrophosphate (PPi) is a physiologic inhibitor of hydroxyapatite mineral precipitation involved in regulating mineralized tissue development and pathologic calcification. Local levels of PPi are controlled by antagonistic functions of factors that decrease PPi and promote mineralization (tissue-nonspecific alkaline phosphatase, ALPL/TNAP), and those that increase local PPi and restrict mineralization (progressive ankylosis protein, ANK; ectonucleotide pyrophosphatase phosphodiesterase-1, NPP1). The cementum enveloping the tooth root is essential for tooth function by providing attachment to the surrounding bone via the nonmineralized periodontal ligament. At present, the developmental regulation of cementum remains poorly understood, hampering efforts for regeneration. To elucidate the role of PPi in cementum formation, we analyzed root development in knock-out ( 2/2) mice featuring PPi dysregulation. Results: Excess PPi in the ALPL 2/2 mouse inhibited cementum formation, causing root detachment consistent with premature tooth loss in the human condition hypophosphatasia, though cementoblast phenotype was unperturbed. Deficient PPi in both Ank and Enpp1 2/2 mice significantly increased cementum apposition and overall thickness more tha

  • tooth root dentin mineralization defects in a mouse model of hypophosphatasia
    Journal of Bone and Mineral Research, 2013
    Co-Authors: Brian L Foster, Francisco H.umberto Nociti, Jose Luis Millan, Kanako J Nagatomo, A B Tran, Sonoko Narisawa, Manisha C Yadav, Martha J Somerman
    Abstract:

    Tissue-nonspecific alkaline phosphatase (TNAP) is expressed in mineralizing tissues and functions to reduce pyrophosphate (PPi), a potent inhibitor of mineralization. Loss of TNAP function causes hypophosphatasia (HPP), a heritable disorder marked by increased PPi, resulting in rickets and osteomalacia. Tooth root cementum defects are well described in both HPP patients and in ALPL−/− mice, a model for infantile HPP. In ALPL−/− mice, dentin mineralization is specifically delayed in the root; however, reports from human HPP patients are variable and inconsistent regarding dentin defects. In the current study, we aimed to define the molecular basis for changes in dentinogenesis observed in ALPL−/− mice. TNAP was found to be highly expressed by mature odontoblasts, and ALPL−/− molar and incisor roots featured defective dentin mineralization, ranging from a mild delay to severely disturbed root dentinogenesis. Lack of mantle dentin mineralization was associated with disordered and dysmorphic odontoblasts having disrupted expression of marker genes osteocalcin and dentin sialophosphoprotein. The formation of, initiation of mineralization within, and rupture of matrix vesicles in ALPL−/− dentin matrix was not affected. Osteopontin (OPN), an inhibitor of mineralization that contributes to the skeletal pathology in ALPL−/− mice, was present in the generally unmineralized ALPL−/− mantle dentin at ruptured mineralizing matrix vesicles, as detected by immunohistochemistry and by immunogold labeling. However, ablating the OPN-encoding Spp1 gene in ALPL−/− mice was insufficient to rescue the dentin mineralization defect. Administration of bioengineered mineral-targeting human TNAP (ENB-0040) to ALPL−/− mice corrected defective dentin mineralization in the molar roots. These studies reveal that TNAP participates in root dentin formation and confirm that reduction of PPi during dentinogenesis is necessary for odontoblast differentiation, dentin matrix secretion, and mineralization. Furthermore, these results elucidate developmental mechanisms underlying dentin pathology in HPP patients, and begin to explain the reported variability in the dentin/pulp complex pathology in these patients. © 2013 American Society for Bone and Mineral Research

  • tooth root dentin mineralization defects in a mouse model of hypophosphatasia
    Journal of Bone and Mineral Research, 2013
    Co-Authors: Brian L Foster, Francisco H.umberto Nociti, Jose Luis Millan, Kanako J Nagatomo, A B Tran, Sonoko Narisawa, Manisha C Yadav, H W Tso, Martha J Somerman
    Abstract:

    Tissue-nonspecific alkaline phosphatase (TNAP) is expressed in mineralizing tissues and functions to reduce pyrophosphate (PP(i) ), a potent inhibitor of mineralization. Loss of TNAP function causes hypophosphatasia (HPP), a heritable disorder marked by increased PP(i) , resulting in rickets and osteomalacia. Tooth root cementum defects are well described in both HPP patients and in ALPL(-/-) mice, a model for infantile HPP. In ALPL(-/-) mice, dentin mineralization is specifically delayed in the root; however, reports from human HPP patients are variable and inconsistent regarding dentin defects. In the current study, we aimed to define the molecular basis for changes in dentinogenesis observed in ALPL(-/-) mice. TNAP was found to be highly expressed by mature odontoblasts, and ALPL(-/-) molar and incisor roots featured defective dentin mineralization, ranging from a mild delay to severely disturbed root dentinogenesis. Lack of mantle dentin mineralization was associated with disordered and dysmorphic odontoblasts having disrupted expression of marker genes osteocalcin and dentin sialophosphoprotein. The formation of, initiation of mineralization within, and rupture of matrix vesicles in ALPL(-/-) dentin matrix was not affected. Osteopontin (OPN), an inhibitor of mineralization that contributes to the skeletal pathology in ALPL(-/-) mice, was present in the generally unmineralized ALPL(-/-) mantle dentin at ruptured mineralizing matrix vesicles, as detected by immunohistochemistry and by immunogold labeling. However, ablating the OPN-encoding Spp1 gene in ALPL(-/-) mice was insufficient to rescue the dentin mineralization defect. Administration of bioengineered mineral-targeting human TNAP (ENB-0040) to ALPL(-/-) mice corrected defective dentin mineralization in the molar roots. These studies reveal that TNAP participates in root dentin formation and confirm that reduction of PP(i) during dentinogenesis is necessary for odontoblast differentiation, dentin matrix secretion, and mineralization. Furthermore, these results elucidate developmental mechanisms underlying dentin pathology in HPP patients, and begin to explain the reported variability in the dentin/pulp complex pathology in these patients.

  • enzyme replacement prevents enamel defects in hypophosphatasia mice
    Journal of Bone and Mineral Research, 2012
    Co-Authors: Manisha C Yadav, Brian L Foster, Sonoko Narisawa, Martha J Somerman, Rodrigo Cardoso De Oliveira, Hanson Fong, Esther Cory, Robert L Sah, Michael P. Whyte
    Abstract:

    Hypophosphatasia (HPP) is the inborn error of metabolism characterized by deficiency of alkaline phosphatase activity, leading to rickets or osteomalacia and to dental defects. HPP occurs from loss-of-function mutations within the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNAP). TNAP knockout (ALPL−/−, aka Akp2−/−) mice closely phenocopy infantile HPP, including the rickets, vitamin B6-responsive seizures, improper dentin mineralization, and lack of acellular cementum. Here, we report that lack of TNAP in ALPL−/− mice also causes severe enamel defects, which are preventable by enzyme replacement with mineral-targeted TNAP (ENB-0040). Immunohistochemistry was used to map the spatiotemporal expression of TNAP in the tissues of the developing enamel organ of healthy mouse molars and incisors. We found strong, stage-specific expression of TNAP in ameloblasts. In the ALPL−/− mice, histological, µCT, and scanning electron microscopy analysis showed reduced mineralization and disrupted organization of the rods and inter-rod structures in enamel of both the molars and incisors. All of these abnormalities were prevented in mice receiving from birth daily subcutaneous injections of mineral-targeting, human TNAP at 8.2 mg/kg/day for up to 44 days. These data reveal an important role for TNAP in enamel mineralization and demonstrate the efficacy of mineral-targeted TNAP to prevent enamel defects in HPP. © 2012 American Society for Bone and Mineral Research.

Manisha C Yadav - One of the best experts on this subject based on the ideXlab platform.

  • conditional ALPL ablation phenocopies dental defects of hypophosphatasia
    Journal of Dental Research, 2017
    Co-Authors: Brian L Foster, Sonoko Narisawa, Manisha C Yadav, Martha J Somerman, Esther Cory, Robert L Sah, Pia Kuss, T N Kolli, L Lukashova, Jose Luis Millan
    Abstract:

    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.

  • enzyme replacement for craniofacial skeletal defects and craniosynostosis in murine hypophosphatasia
    Bone, 2015
    Co-Authors: Jin Liu, Hwa Kyung Nam, Cassie Campbell, Jose Luis Millan, Manisha C Yadav, Alexandre Caron, Nan E Hatch
    Abstract:

    Hypophosphatasia (HPP) is an inborn-error-of-metabolism disorder characterized by deficient bone and tooth mineralization due to loss-of function mutations in the gene (ALPL) encoding tissue-nonspecific alkaline phosphatase (TNAP). ALPL(-/-) mice exhibit many characteristics seen in infantile HPP including long bone and tooth defects, vitamin B6 responsive seizures and craniosynostosis. Previous reports demonstrated that a mineral-targeted form of TNAP rescues long bone, vertebral and tooth mineralization defects in ALPL(-/-) mice. Here we report that enzyme replacement with mineral-targeted TNAP (asfotase-alfa) also prevents craniosynostosis (the premature fusion of cranial bones) and additional craniofacial skeletal abnormalities in ALPL(-/-) mice. Craniosynostosis, cranial bone volume and density, and craniofacial shape abnormalities were assessed by microscopy, histology, digital caliper measurements and micro CT. We found that craniofacial shape defects, cranial bone mineralization and craniosynostosis were corrected in ALPL(-/-) mice injected daily subcutaneously starting at birth with recombinant enzyme. Analysis of ALPL(-/-) calvarial cells indicates that TNAP deficiency leads to aberrant osteoblastic gene expression and diminished proliferation. Some but not all of these cellular abnormalities were rescued by treatment with inorganic phosphate. These results confirm an essential role for TNAP in craniofacial skeletal development and demonstrate the efficacy of early postnatal mineral-targeted enzyme replacement for preventing craniofacial abnormalities including craniosynostosis in murine infantile HPP.

  • improvement of the skeletal and dental hypophosphatasia phenotype in ALPL mice by administration of soluble non targeted chimeric alkaline phosphatase
    Bone, 2015
    Co-Authors: Kellen Cristina Da Silva Gasque, Nan E Hatch, Jin Liu, Brian L Foster, Manisha C Yadav, Martha J Somerman, Pia Kuss, Tina Kiffermoreira, Andrea Van Elsas, Jose Luis Millan
    Abstract:

    Abstract Hypophosphatasia (HPP) results from ALPL gene mutations, which lead to a deficiency of tissue-nonspecific alkaline phosphatase (TNAP), and accumulation of inorganic pyrophosphate, a potent inhibitor of mineralization that is also a natural substrate of TNAP, in the extracellular space. HPP causes mineralization disorders including soft bones (rickets or osteomalacia) and defects in teeth and periodontal tissues. Enzyme replacement therapy using mineral-targeting recombinant TNAP has proven effective in preventing skeletal and dental defects in TNAP knockout ( ALPL −/− ) mice, a model for life-threatening HPP. Here, we show that the administration of a soluble, intestinal-like chimeric alkaline phosphatase (ChimAP) improves the manifestations of HPP in ALPL −/− mice. Mice received daily subcutaneous injections of ChimAP at doses of 1, 8 or 16 mg/kg, from birth for up to 53 days. Lifespan and body weight of ALPL −/− mice were normalized, and vitamin B6-associated seizures were absent with 16 mg/kg/day of ChimAP. Radiographs, μCT and histological analyses documented improved mineralization in cortical and trabecular bone and secondary ossification centers in long bones of ChimAP16-treated mice. There was no evidence of craniosynostosis in the ChimAP16-treated mice and we did not detect ectopic calcification by radiography and histology in the aortas, stomachs, kidneys or lungs in any of the treatment groups. Molar tooth development and function improved with the highest ChimAP dose, including enamel, dentin, and tooth morphology. Cementum remained deficient and alveolar bone mineralization was reduced compared to controls, though ChimAP-treated ALPL −/− mice featured periodontal attachment and retained teeth. This study provides the first evidence for the pharmacological efficacy of ChimAP for use in the treatment of skeletal and dental manifestations of HPP.

  • tooth root dentin mineralization defects in a mouse model of hypophosphatasia
    Journal of Bone and Mineral Research, 2013
    Co-Authors: Brian L Foster, Francisco H.umberto Nociti, Jose Luis Millan, Kanako J Nagatomo, A B Tran, Sonoko Narisawa, Manisha C Yadav, Martha J Somerman
    Abstract:

    Tissue-nonspecific alkaline phosphatase (TNAP) is expressed in mineralizing tissues and functions to reduce pyrophosphate (PPi), a potent inhibitor of mineralization. Loss of TNAP function causes hypophosphatasia (HPP), a heritable disorder marked by increased PPi, resulting in rickets and osteomalacia. Tooth root cementum defects are well described in both HPP patients and in ALPL−/− mice, a model for infantile HPP. In ALPL−/− mice, dentin mineralization is specifically delayed in the root; however, reports from human HPP patients are variable and inconsistent regarding dentin defects. In the current study, we aimed to define the molecular basis for changes in dentinogenesis observed in ALPL−/− mice. TNAP was found to be highly expressed by mature odontoblasts, and ALPL−/− molar and incisor roots featured defective dentin mineralization, ranging from a mild delay to severely disturbed root dentinogenesis. Lack of mantle dentin mineralization was associated with disordered and dysmorphic odontoblasts having disrupted expression of marker genes osteocalcin and dentin sialophosphoprotein. The formation of, initiation of mineralization within, and rupture of matrix vesicles in ALPL−/− dentin matrix was not affected. Osteopontin (OPN), an inhibitor of mineralization that contributes to the skeletal pathology in ALPL−/− mice, was present in the generally unmineralized ALPL−/− mantle dentin at ruptured mineralizing matrix vesicles, as detected by immunohistochemistry and by immunogold labeling. However, ablating the OPN-encoding Spp1 gene in ALPL−/− mice was insufficient to rescue the dentin mineralization defect. Administration of bioengineered mineral-targeting human TNAP (ENB-0040) to ALPL−/− mice corrected defective dentin mineralization in the molar roots. These studies reveal that TNAP participates in root dentin formation and confirm that reduction of PPi during dentinogenesis is necessary for odontoblast differentiation, dentin matrix secretion, and mineralization. Furthermore, these results elucidate developmental mechanisms underlying dentin pathology in HPP patients, and begin to explain the reported variability in the dentin/pulp complex pathology in these patients. © 2013 American Society for Bone and Mineral Research

  • tooth root dentin mineralization defects in a mouse model of hypophosphatasia
    Journal of Bone and Mineral Research, 2013
    Co-Authors: Brian L Foster, Francisco H.umberto Nociti, Jose Luis Millan, Kanako J Nagatomo, A B Tran, Sonoko Narisawa, Manisha C Yadav, H W Tso, Martha J Somerman
    Abstract:

    Tissue-nonspecific alkaline phosphatase (TNAP) is expressed in mineralizing tissues and functions to reduce pyrophosphate (PP(i) ), a potent inhibitor of mineralization. Loss of TNAP function causes hypophosphatasia (HPP), a heritable disorder marked by increased PP(i) , resulting in rickets and osteomalacia. Tooth root cementum defects are well described in both HPP patients and in ALPL(-/-) mice, a model for infantile HPP. In ALPL(-/-) mice, dentin mineralization is specifically delayed in the root; however, reports from human HPP patients are variable and inconsistent regarding dentin defects. In the current study, we aimed to define the molecular basis for changes in dentinogenesis observed in ALPL(-/-) mice. TNAP was found to be highly expressed by mature odontoblasts, and ALPL(-/-) molar and incisor roots featured defective dentin mineralization, ranging from a mild delay to severely disturbed root dentinogenesis. Lack of mantle dentin mineralization was associated with disordered and dysmorphic odontoblasts having disrupted expression of marker genes osteocalcin and dentin sialophosphoprotein. The formation of, initiation of mineralization within, and rupture of matrix vesicles in ALPL(-/-) dentin matrix was not affected. Osteopontin (OPN), an inhibitor of mineralization that contributes to the skeletal pathology in ALPL(-/-) mice, was present in the generally unmineralized ALPL(-/-) mantle dentin at ruptured mineralizing matrix vesicles, as detected by immunohistochemistry and by immunogold labeling. However, ablating the OPN-encoding Spp1 gene in ALPL(-/-) mice was insufficient to rescue the dentin mineralization defect. Administration of bioengineered mineral-targeting human TNAP (ENB-0040) to ALPL(-/-) mice corrected defective dentin mineralization in the molar roots. These studies reveal that TNAP participates in root dentin formation and confirm that reduction of PP(i) during dentinogenesis is necessary for odontoblast differentiation, dentin matrix secretion, and mineralization. Furthermore, these results elucidate developmental mechanisms underlying dentin pathology in HPP patients, and begin to explain the reported variability in the dentin/pulp complex pathology in these patients.