title: Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization.
abstract: Osteoblasts mineralize bone matrix by promoting hydroxyapatite crystal formation and growth in the interior of membrane-limited matrix vesicles (MVs) and by propagating the crystals onto the collagenous extracellular matrix. Two osteoblast proteins, tissue-nonspecific alkaline phosphatase (TNAP) and plasma cell membrane glycoprotein-1 (PC-1) are involved in this process. Mutations in the TNAP gene result in the inborn error of metabolism known as hypophosphatasia, characterized by poorly mineralized bones, spontaneous fractures, and elevated extracellular concentrations of inorganic pyrophosphate (PP(i)). PP(i) suppresses the formation and growth of hydroxyapatite crystals. PP(i) is produced by the nucleoside triphosphate pyrophosphohydrolase activity of a family of isozymes, with PC-1 being the only member present in MVs. Mice with spontaneous mutations in the PC-1 gene have hypermineralization abnormalities that include osteoarthritis and ossification of the posterior longitudinal ligament of the spine. Here, we show the respective correction of bone mineralization abnormalities in knockout mice null for both the TNAP (Akp2) and PC-1 (Enpp1) genes. Each allele of Akp2 and Enpp1 has a measurable influence on mineralization status in vivo. Ex vivo experiments using cultured double-knockout osteoblasts and their MVs demonstrate normalization of PP(i) content and mineral deposition. Our data provide evidence that TNAP and PC-1 are key regulators of the extracellular PP(i) concentrations required for controlled bone mineralization. Our results suggest that inhibiting PC-1 function may be a viable therapeutic strategy for hypophosphatasia. Conversely, interfering with TNAP activity may correct pathological hyperossification because of PP(i) insufficiency.
authors.affiliation: The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Lovisa
authors.initials: L
authors.lastname: Hessle
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Johnson
authors.forename: H Clarke
authors.initials: HC
authors.lastname: Anderson
authors.forename: Sonoko
authors.initials: S
authors.lastname: Narisawa
authors.forename: Adnan
authors.initials: A
authors.lastname: Sali
authors.forename: James W
authors.initials: JW
authors.lastname: Goding
authors.forename: Robert
authors.initials: R
authors.lastname: Terkeltaub
authors.forename: José Luis
authors.initials: JL
authors.lastname: Millan
mesh_terms: D000469:Alkaline Phosphatase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002113:Calcification, Physiologic / Q000502:physiology*; D011756:Diphosphates / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism; D010018:Osteomalacia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010727:Phosphoric Diester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011755:Pyrophosphatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012279:Rickets / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution
chemical_list: D011756:Diphosphates; D000469:Alkaline Phosphatase; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases