Periodontal defects in the A116T knock-in murine model of odontohypophosphatasia

B. L. Foster, C. R. Sheen, N. E. Hatch, J. Liu, E. Cory, S. Narisawa, T. Kiffer-Moreira, R. L. Sah, M. P. Whyte, M. J. Somerman, J. L. Millán

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21 Scopus citations


Mutations in ALPL result in hypophosphatasia (HPP), a disease causing defective skeletal mineralization. ALPL encodes tissue nonspecific alkaline phosphatase (ALP), an enzyme that promotes mineralization by reducing inorganic pyrophosphate, a mineralization inhibitor. In addition to skeletal defects, HPP causes dental defects, and a mild clinical form of HPP, odontohypophosphatasia, features only a dental phenotype. The Alpl knockout (Alpl-/-) mouse phenocopies severe infantile HPP, including profound skeletal and dental defects. However, the severity of disease in Alpl-/- mice prevents analysis at advanced ages, including studies to target rescue of dental tissues. We aimed to generate a knock-in mouse model of odontohypophosphatasia with a primarily dental phenotype, based on a mutation (c.346G>A) identified in a human kindred with autosomal dominant odontohypophosphatasia. Biochemical, skeletal, and dental analyses were performed on the resulting Alpl+/A116T mice to validate this model. Alpl+/A116T mice featured 50% reduction in plasma ALP activity compared with wild-type controls. No differences in litter size, survival, or body weight were observed in Alpl+/A116T versus wild-type mice. The postcranial skeleton of Alpl+/A116T mice was normal by radiography, with no differences in femur length, cortical/trabecular structure or mineral density, or mechanical properties. Parietal bone trabecular compartment was mildly altered. Alpl+/A116T mice featured alterations in the alveolar bone, including radiolucencies and resorptive lesions, osteoid accumulation on the alveolar bone crest, and significant differences in several bone properties measured by micro-computed tomography. Nonsignificant changes in acellular cementum did not appear to affect periodontal attachment or function, although circulating ALP activity was correlated significantly with incisor cementum thickness. The Alpl+/A116T mouse is the first model of odontohypophosphatasia, providing insights on dentoalveolar development and function under reduced ALP, bringing attention to direct effects of HPP on alveolar bone, and offering a new model for testing potential dental-targeted therapies in future studies.

Original languageEnglish
Pages (from-to)706-714
Number of pages9
JournalJournal of Dental Research
Issue number5
StatePublished - May 9 2015


  • alkaline phosphatase
  • bone
  • cementum
  • dentin
  • hypophosphatasia
  • periodontium

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    Foster, B. L., Sheen, C. R., Hatch, N. E., Liu, J., Cory, E., Narisawa, S., Kiffer-Moreira, T., Sah, R. L., Whyte, M. P., Somerman, M. J., & Millán, J. L. (2015). Periodontal defects in the A116T knock-in murine model of odontohypophosphatasia. Journal of Dental Research, 94(5), 706-714.