Periodontal Defects in the A116T Knock-in Murine Model of Odontohypophosphatasia.

Abstract

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.

• Authors: 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
• Journal: Journal of dental research (J Dent Res) Vol. 94 Issue 5 Pg. 706-14 (May 2015) ISSN: 1544-0591 [Electronic] United States
• PMID: 25716980 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © International & American Associations for Dental Research 2015.

Chemical References

• Alkaline Phosphatase
• Adenine
• Thymine

Topics

• Adenine
• Alkaline Phosphatase (genetics)
• Alveolar Process (pathology)
• Animals
• Biomechanical Phenomena
• Bone Density (physiology)
• Bone Matrix (pathology)
• Bone Resorption (pathology)
• Calcification, Physiologic (physiology)
• Dental Cementum (pathology)
• Disease Models, Animal
• Femur (physiopathology)
• Gene Knock-In Techniques (methods)
• Humans
• Hypophosphatasia (genetics)
• Male
• Mandible (pathology)
• Mice
• Parietal Bone (pathology)
• Periodontal Diseases (genetics)
• Pliability
• Thymine
• Tooth Demineralization (congenital, genetics)
• X-Ray Microtomography (methods)