title: 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(-/-)) phenocopy human infantile hypophosphatasia; they develop rickets at 1 week of age, and die before being weaned, having severe skeletal and dental hypomineralization and episodes of apnea and vitamin B(6)-responsive seizures. Delay and defects in dentin mineralization, together with a deficiency in acellular cementum, are characteristic. We report the prevention of these dental abnormalities in Akp2(-/-) mice receiving treatment from birth with daily injections of a mineral-targeting, human TNALP (sALP-FcD(10)). sALP-FcD(10) prevented hypomineralization of alveolar bone, dentin, and cementum as assessed by micro-computed tomography and histology. Osteopontin--a marker of acellular cementum--was immuno-localized along root surfaces, confirming that acellular cementum, typically missing or reduced in Akp2(-/-) mice, formed normally. Our findings provide insight concerning how acellular cementum is formed on tooth surfaces to effect periodontal ligament attachment to retain teeth in their osseous alveolar sockets. Furthermore, they provide evidence that this enzyme-replacement therapy, applied early in post-natal life--where the majority of tooth root development occurs, including acellular cementum formation--could prevent the accelerated tooth loss seen in individuals with HPP.
authors.affiliation: Faculty of Dentistry, and Department of Anatomy and Cell Biology, McGill University, Strathcona Anatomy and Dentistry Bldg, 3640 University Street, Montreal, Quebec, Canada. marc.mckee@mcgill.ca
authors.forename: M D
authors.initials: MD
authors.lastname: McKee
authors.forename: Y
authors.initials: Y
authors.lastname: Nakano
authors.forename: D L
authors.initials: DL
authors.lastname: Masica
authors.forename: J J
authors.initials: JJ
authors.lastname: Gray
authors.forename: I
authors.initials: I
authors.lastname: Lemire
authors.forename: R
authors.initials: R
authors.lastname: Heft
authors.forename: M P
authors.initials: MP
authors.lastname: Whyte
authors.forename: P
authors.initials: P
authors.lastname: Crine
authors.forename: J L
authors.initials: JL
authors.lastname: Millán
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics* / Q000627:therapeutic use*; D000539:Alveolar Process / Q000187:drug effects / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D002113:Calcification, Physiologic / Q000187:drug effects; D025021:Cementogenesis / Q000187:drug effects; D003461:Crystallography; D003739:Dental Cementum / Q000187:drug effects / Q000473:pathology; D003804:Dentin / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D017886:Durapatite / Q000737:chemistry; D056947:Enzyme Replacement Therapy; D006801:Humans; D007014:Hypophosphatasia / Q000188:drug therapy* / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009805:Odontogenesis / Q000187:drug effects; D053495:Osteopontin / Q000032:analysis; D010513:Periodontal Ligament / Q000187:drug effects / Q000473:pathology; D014071:Tooth Abnormalities / Q000517:prevention & control*; D014074:Tooth Calcification / Q000187:drug effects; D014092:Tooth Root / Q000187:drug effects / Q000473:pathology; D020390:Tooth Socket / Q000187:drug effects / Q000473:pathology; D055114:X-Ray Microtomography
chemical_list: C506896:Spp1 protein, mouse; D053495:Osteopontin; D017886:Durapatite; C548267:ALPL protein, human; C510878:ALPL protein, mouse; D000469:Alkaline Phosphatase