title: Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia.
abstract: Hypophosphatasia is an inborn error of metabolism characterized by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) and skeletal disease due to impaired mineralization of cartilage and bone matrix. We investigated two independently generated TNSALP gene knock-out mouse strains as potential models for hypophosphatasia. Homozygous mice (-/-) had < 1% of wild-type plasma TNSALP activity; heterozygotes had the predicted mean of approximately 50%. Phosphoethanolamine, inorganic pyrophosphate, and pyridoxal 5'-phosphate are putative natural substrates for TNSALP and all were increased endogenously in the knock-out mice. Skeletal disease first appeared radiographically at approximately 10 days of age and featured worsening rachitic changes, osteopenia, and fracture. Histologic studies revealed developmental arrest of chondrocyte differentiation in epiphyses and in growth plates with diminished or absent hypertrophic zones. Progressive osteoidosis from defective skeletal matrix mineralization was noted but not associated with features of secondary hyperparathyroidism. Plasma and urine calcium and phosphate levels were unremarkable. Our findings demonstrate that TNSALP knock-out mice are a good model for the infantile form of hypophosphatasia and provide compelling evidence for an important role for TNSALP in postnatal development and mineralization of the murine skeleton.
authors.affiliation: Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri, USA.
authors.forename: K N
authors.initials: KN
authors.lastname: Fedde
authors.forename: L
authors.initials: L
authors.lastname: Blair
authors.forename: J
authors.initials: J
authors.lastname: Silverstein
authors.forename: S P
authors.initials: SP
authors.lastname: Coburn
authors.forename: L M
authors.initials: LM
authors.lastname: Ryan
authors.forename: R S
authors.initials: RS
authors.lastname: Weinstein
authors.forename: K
authors.initials: K
authors.lastname: Waymire
authors.forename: S
authors.initials: S
authors.lastname: Narisawa
authors.forename: J L
authors.initials: JL
authors.lastname: Millán
authors.forename: G R
authors.initials: GR
authors.lastname: MacGregor
authors.forename: M P
authors.initials: MP
authors.lastname: Whyte
mesh_terms: D000367:Age Factors; D000469:Alkaline Phosphatase / Q000097:blood / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000235:genetics; D004195:Disease Models, Animal; D006579:Heterozygote; D006614:Hindlimb / Q000000981:diagnostic imaging / Q000254:growth & development; D006651:Histocytochemistry; D006720:Homozygote; D007014:Hypophosphatasia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010710:Phosphates / Q000652:urine; D010714:Phosphatidylethanolamines / Q000652:urine; D011732:Pyridoxal Phosphate / Q000097:blood; D011859:Radiography; D013977:Tibia / Q000000981:diagnostic imaging / Q000254:growth & development
chemical_list: D010710:Phosphates; D010714:Phosphatidylethanolamines; D011732:Pyridoxal Phosphate; D000469:Alkaline Phosphatase