Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia

Hypophosphatasia is an inborn error of metabolism characterized by deficien t activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNS ALP) and skeletal disease due to impaired mineralization of cartilage and b one matrix. We investigated two independently generated TNSALP gene knock-o ut mouse strains as potential models for hypophosphatasia. Homozygous mice (-/-) had <1% of wild-type plasma TNSALP activity; heterozygotes had the pr edicted mean of similar to 50%, Phosphoethanolamine, inorganic pyrophosphat e, and pyridoxal 5'- phosphate are putative natural substrates for TNSALP a nd all were increased endogenously in the knock-out mice. Skeletal disease first appeared radiographically at similar to 10 days of age and featured w orsening rachitic changes, osteopenia, and fracture. Histologic studies rev ealed 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 urin e calcium and phosphate levels were unremarkable. Our findings demonstrate that TNSALP knock-out mice are a good model for the infantile form of hypop hosphatasia and provide compelling evidence for an important role for TNSAL P in postnatal development and mineralization of the murine skeleton.