Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia. J Bone Miner Res 1999 Dec;14(12):2015-26
Date
01/05/2000Pubmed ID
10620060Pubmed Central ID
PMC3049802DOI
10.1359/jbmr.1999.14.12.2015Scopus ID
2-s2.0-0033386205 (requires institutional sign-in at Scopus site) 334 CitationsAbstract
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.
Author List
Fedde KN, Blair L, Silverstein J, Coburn SP, Ryan LM, Weinstein RS, Waymire K, Narisawa S, Millán JL, MacGregor GR, Whyte MPMESH terms used to index this publication - Major topics in bold
Age FactorsAlkaline Phosphatase
Animals
Animals, Newborn
Body Weight
Disease Models, Animal
Heterozygote
Hindlimb
Histocytochemistry
Homozygote
Hypophosphatasia
Mice
Mice, Knockout
Phosphates
Phosphatidylethanolamines
Pyridoxal Phosphate
Radiography
Tibia