title: Compounded PHOSPHO1/ALPL deficiencies reduce dentin mineralization.
abstract: Phosphatases are involved in bone and tooth mineralization, but their mechanisms of action are not completely understood. Tissue-nonspecific alkaline phosphatase (TNAP, ALPL) regulates inhibitory extracellular pyrophosphate through its pyrophosphatase activity to control mineral propagation in the matrix; mice without TNAP lack acellular cementum, and have mineralization defects in dentin, enamel, and bone. PHOSPHO1 is a phosphatase found within membrane-bounded matrix vesicles in mineralized tissues, and double ablation of Alpl and Phospho1 in mice leads to a complete absence of skeletal mineralization. Here, we describe mineralization abnormalities in the teeth of Phospho1(-/-) mice, and in compound knockout mice lacking Phospho1 and one allele of Alpl (Phospho1(-/-);Alpl(+/-) ). In wild-type mice, PHOSPHO1 and TNAP co-localized to odontoblasts at early stages of dentinogenesis, coincident with the early mineralization of mantle dentin. In Phospho1 knockout mice, radiography, micro-computed tomography, histology, and transmission electron microscopy all demonstrated mineralization abnormalities of incisor dentin, with the most remarkable findings being reduced overall mineralization coincident with decreased matrix vesicle mineralization in the Phospho1(-/-) mice, and the almost complete absence of matrix vesicles in the Phospho1(-/-);Alpl(+/-) mice, whose incisors showed a further reduction in mineralization. Results from this study support prominent non-redundant roles for both PHOSPHO1 and TNAP in dentin mineralization.
authors.affiliation: Faculty of Dentistry, and Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, 3640 University Street, Montreal, QC, Canada. marc.mckee@mcgill.ca
authors.forename: M D
authors.initials: MD
authors.lastname: McKee
authors.forename: M C
authors.initials: MC
authors.lastname: Yadav
authors.forename: B L
authors.initials: BL
authors.lastname: Foster
authors.forename: M J
authors.initials: MJ
authors.lastname: Somerman
authors.forename: C
authors.initials: C
authors.lastname: Farquharson
authors.forename: J L
authors.initials: JL
authors.lastname: Millán
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics*; D000483:Alleles; D000539:Alveolar Process / Q000201:enzymology; D000565:Ameloblasts / Q000201:enzymology; D000818:Animals; D001031:Apatites / Q000032:analysis; D002113:Calcification, Physiologic / Q000235:genetics; D003804:Dentin / Q000201:enzymology*; D003810:Dentinogenesis / Q000235:genetics; D004658:Enamel Organ / Q000201:enzymology; D005109:Extracellular Matrix / Q000201:enzymology; D007150:Immunohistochemistry; D007180:Incisor / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D046529:Microscopy, Electron, Transmission; D008963:Molar / Q000201:enzymology; D009804:Odontoblasts / Q000201:enzymology; D010006:Osteoblasts / Q000201:enzymology; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D011856:Radiographic Image Enhancement; D014074:Tooth Calcification / Q000235:genetics*; D014083:Tooth Germ / Q000201:enzymology; D055114:X-Ray Microtomography
chemical_list: D001031:Apatites; C552022:PHOSPHO1 protein, mouse; C510878:ALPL protein, mouse; D000469:Alkaline Phosphatase; D010744:Phosphoric Monoester Hydrolases
keywords: extracellular matrix; extracellular matrix proteins; matrix vesicles; phosphatase; tissue-non-specific alkaline phosphatase; tooth