Enzyme Replacement Therapy Prevents Dental Defects in a Model of Hypophosphatasia

McKee, Marc D.; Nakano, Yukiko; Masica, David L.; Gray, Jeffrey J.; Lemire, Isabelle; Heft, R.; Whyte, Michael P.; Crine, Philippe; Millán, José Luis

doi:10.1177/0022034510393517

Cited by 107 publications

(118 citation statements)

References 33 publications

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“…Local TNAP deficiency (by IHC), hypophosphatemia, and hypocalcemia were ruled out as causes of cementum inhibition in Bsp -/-mice. It is notable that acellular cementum formation is similarly inhibited in the Alpl -/-mouse model featuring loss of TNAP function (Beertsen et al, 1999;McKee et al, 2011;Foster et al, 2012). Alpl -/-mice harbor increased levels of the mineral inhibitor pyrophosphate (PP i ) and serve as a model of hypophosphatasia (HPP), where lack of acellular cementum predisposes to tooth loss (van den Bos et al, 2005).…”

Section: Acellular Cementum As a Mineralization-sensitive Tissuementioning

confidence: 99%

Deficiency in Acellular Cementum and Periodontal Attachment in Bsp Null Mice

et al. 2012

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A supplemental appendix to this article is published electronically only at http://jdr.sagepub.com/supplemental. ABSTRACTBone sialoprotein (BSP) is an extracellular matrix protein found in mineralized tissues of the skeleton and dentition. BSP is multifunctional, affecting cell attachment and signaling through an RGD integrin-binding region, and acting as a positive regulator for mineral precipitation by nucleating hydroxyapatite crystals. BSP is present in cementum, the hard tissue covering the tooth root that anchors periodontal ligament (PDL) attachment. To test our hypothesis that BSP plays an important role in cementogenesis, we analyzed tooth development in a Bsp null ( -/-) mouse model. Developmental analysis by histology, histochemistry, and SEM revealed a significant reduction in acellular cementum formation on Bsp -/-mouse molar and incisor roots, and the cementum deposited appeared hypomineralized. Structural defects in cementum-PDL interfaces in Bsp -/-mice caused PDL detachment, likely contributing to the high incidence of incisor malocclusion. Loss of BSP caused progressively disorganized PDL and significantly increased epithelial down-growth with aging. Bsp -/-mice displayed extensive root and alveolar bone resorption, mediated by increased RANKL and the presence of osteoclasts. Results collected here suggest that BSP plays a non-redundant role in acellular cementum formation, likely involved in initiating mineralization on the root surface. Through its importance to cementum integrity, BSP is essential for periodontal function.KEY WORDS: bone sialoprotein, cementum, periodontal ligament, bone, alkaline phosphatase, extracellular matrix.

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Section: Acellular Cementum As a Mineralization-sensitive Tissuementioning

confidence: 99%

Deficiency in Acellular Cementum and Periodontal Attachment in Bsp Null Mice

et al. 2012

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“…24 In Tnsalp knockout mice, which constitute an animal model of infantile hypophosphatasia, 25 treatment with daily subcutaneous injections of ENB-0040 at doses that result in serum levels ranging from 650 to 1000 U per liter preserve the mineralization of bones and teeth. 24,26,27 A phase 1 study involving adult patients with hypophosphatasia showed peak and trough ENB-0040 levels in this range after one intravenous dose of 3 mg per kilogram of body weight and weekly subcutaneous doses of 2 mg per kilogram. 28 We conducted a clinical trial of treatment with ENB-0040 for at least 1 year in infants and young children with life-threatening hypophosphatasia.…”

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Enzyme-Replacement Therapy in Life-Threatening Hypophosphatasia

Greenberg²,

et al. 2012

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“…Defects in cementum, dentin, alveolar bone, and enamel have been demonstrated in Alpl -/-mice (McKee et al 2011;Foster et al 2012;Yadav et al 2012;Foster, Nagatomo, et al 2013;Zweifler et al 2015). However, these mice die by 2 to 3 wk of age, thereby preventing analysis of HPP-associated pathologies at advanced ages.…”

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Conditional Alpl Ablation Phenocopies Dental Defects of Hypophosphatasia

et al. 2016

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

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Enzyme Replacement Therapy Prevents Dental Defects in a Model of Hypophosphatasia

Abstract: Hypophosphatasia (HPP) occurs from loss-of-function mutation in the tissue-non-specific alkaline phosphatase (TNALP) gene, resulting in extracellular pyrophosphate accumulation that inhibits skeletal and dental mineralization. TNALP-null mice (Akp2

Cited by 107 publications

References 33 publications

Deficiency in Acellular Cementum and Periodontal Attachment in Bsp Null Mice

Deficiency in Acellular Cementum and Periodontal Attachment in Bsp Null Mice

Enzyme-Replacement Therapy in Life-Threatening Hypophosphatasia

Conditional Alpl Ablation Phenocopies Dental Defects of Hypophosphatasia

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