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Enzyme replacement prevents enamel defects in hypophosphatasia mice.

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.

SUBMITTER: Yadav MC

PROVIDER: S-EPMC3395779 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Enzyme replacement prevents enamel defects in hypophosphatasia mice.

Yadav Manisha C MC de Oliveira Rodrigo Cardoso RC Foster Brian L BL Fong Hanson H Cory Esther E Narisawa Sonoko S Sah Robert L RL Somerman Martha M Whyte Michael P MP Millán José Luis JL

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20120801 8

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 ...[more]

PMID: 22461224

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Project description:BackgroundHypophosphatasia (HPP), a skeletal disease characterized by hypomineralization of bone and teeth, is caused by an ALPL gene mutation that leads to low activity of the tissue non-specific alkaline phosphatase enzyme. Although enzyme replacement therapy (ERT) was recently introduced for affected patients, no known studies have been reported regarding its dental effects related to permanent teeth and jaw bones. In the present study, we examined the dental effects of ERT in a case of childhood-type hypophosphatasia, including panoramic radiography findings used to estimate the dental age of permanent teeth and mandibular bone density. Furthermore, the effects of that therapy on the periodontal condition of the patient were evaluated by comparing periodontal pocket depth before and after initiation.Case presentationAn 11-year-1-month-old boy was referred to our clinic for consultation regarding oral management. Two primary incisors had spontaneously exfoliated at 1 year 8 months old and he had been diagnosed with childhood-type HPP at the age of 2 years 2 months. Obvious symptoms were localized in the dental region at the time of diagnosis, though later extended to other parts of the body such as bone pain. ERT was started at 11 years 7 months of age, after which bone pain disappeared, and motor functions and activities of daily living improved. We estimated dental age based on tooth development stage. The age gap between chronological and dental ages was expanded before treatment, and then showed a constant decrease after ERT initiation and finally disappeared. The index for mandibular bone density (mandibular cortical width / length from mesial buccal cusp to apex of first molar) was increased after ERT initiation. Furthermore, the periodontal condition for all teeth except those exfoliated was stable after starting therapy.ConclusionsERT resulted in improved tooth and mandibular bone mineralization, with notably good effects on teeth under formation. Acceleration of mineralization of roots associated with erupting teeth leads to stabilization of the periodontal condition. We concluded that ERT contributed to the improved dental condition seen in this patient.

Project description:Dentin sialophosphoprotein (DSPP) is an extracellular matrix protein that is highly expressed in odontoblasts, but only transiently expressed in presecretory ameloblasts during tooth development. We previously generated a knockin mouse model expressing a mouse equivalent (DSPP, p.P19L) of human mutant DSPP (p.P17L; referred to as "DsppP19L/+ "), and reported that DsppP19L/+ and DsppP19L/P19L mice manifested a dentin phenotype resembling human dentinogenesis imperfecta (DGI). In this study, we analyzed pathogenic effects of mutant P19L-DSPP on enamel development in DsppP19L/+ and DsppP19L/P19L mice. Micro-Computed Tomography (μCT) analyses of 7-week-old mouse mandibular incisors showed that DsppP19L/P19L mice had significantly decreased enamel volume and/or enamel density at different stages of amelogenesis examined. Acid-etched scanning electron microscopy (SEM) analyses of mouse incisors demonstrated that, at the mid-late maturation stage of amelogenesis, the enamel of wild-type mice already had apparent decussating pattern of enamel rods, whereas only minute particulates were found in DsppP19L/+ mice, and no discernible structures in DsppP19L/P19L mouse enamel. However, by the time that incisor enamel was about to erupt into oral cavity, distinct decussating enamel rods were evident in DsppP19L/+ mice, but only poorly-defined enamel rods were revealed in DsppP19L/P19L mice. Moreover, μCT analyses of the mandibular first molars showed that DsppP19L/+ and DsppP19L/P19L mice had a significant reduction in enamel volume and enamel density at the ages of 2, 3, and 24weeks after birth. Backscattered and acid-etched SEM analyses revealed that while 3-week-old DsppP19L/+ mice had similar pattern of enamel rods in the mandibular first molars as age-matched wild-type mice, no distinct enamel rods were observed in DsppP19L/P19L mice. Yet neither DsppP19L/+ nor DsppP19L/P19L mice showed well-defined enamel rods in the mandibular first molars by the age of 24weeks, as judged by backscattered and acid-etched SEM. In situ hybridization showed that DSPP mRNA level was markedly reduced in the presecretory ameloblasts, but immunohistochemistry revealed that DSP/DSPP immunostaining signals were much stronger within the presecretory ameloblasts in Dspp mutant mice than in wild-type mice. These results suggest that mutant P19L-DSPP protein caused developmental enamel defects in mice, which may be associated with intracellular retention of mutant DSPP in the presecretory ameloblasts.

Project description: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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Enzyme replacement prevents enamel defects in hypophosphatasia mice.

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Enzyme replacement prevents enamel defects in hypophosphatasia mice.

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