title: 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.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Foster
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Sheen
authors.affiliation: Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
authors.forename: N E
authors.initials: NE
authors.lastname: Hatch
authors.affiliation: Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Cory
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Narisawa
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kiffer-Moreira
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Sah
authors.affiliation: Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Whyte
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Somerman
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA millan@sanfordburnham.org.
authors.forename: J L
authors.initials: JL
authors.lastname: Millán
mesh_terms: D000225:Adenine; D000469:Alkaline Phosphatase / Q000235:genetics; D000539:Alveolar Process / Q000473:pathology; D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000502:physiology; D001857:Bone Matrix / Q000473:pathology; D001862:Bone Resorption / Q000473:pathology; D002113:Calcification, Physiologic / Q000502:physiology; D003739:Dental Cementum / Q000473:pathology; D004195:Disease Models, Animal; D005269:Femur / Q000503:physiopathology; D055879:Gene Knock-In Techniques / Q000379:methods*; D006801:Humans; D007014:Hypophosphatasia / Q000235:genetics*; D008297:Male; D008334:Mandible / Q000473:pathology; D051379:Mice; D010294:Parietal Bone / Q000473:pathology; D010510:Periodontal Diseases / Q000235:genetics*; D018583:Pliability; D013941:Thymine; D017001:Tooth Demineralization / Q000151:congenital* / Q000235:genetics; D055114:X-Ray Microtomography / Q000379:methods
chemical_list: D000469:Alkaline Phosphatase; D000225:Adenine; D013941:Thymine
keywords: alkaline phosphatase; bone; cementum; dentin; hypophosphatasia; periodontium