Genetically modified mice are powerful tools for understanding the functions of genes and
proteins and often serve as models of human disease. Here, several knockout and transgenic mouse lines related to tissue-nonspecific
alkaline phosphatase (TNAP) are described. Conventional TNAP knockout mice die before weaning and show
vitamin B6 dependent
epilepsy and impaired bone mineralization, mimicking
infantile hypophosphatasia. Administration of recombinant human TNAP rescues the lethal phenotype and improves bone mineralization in the null knockout mice, and this
enzyme replacement therapy has been successfully applied to the treatment of human patients. Transgenic expression of human TNAP also rescues the TNAP knockout mice. Studies of the TNAP knockout mice and their double knockouts with
ectonucleotide pyrophosphatase/phosphodiesterase 1 or progressive
ankylosis protein revealed that
pyridoxal phosphate and inorganic
pyrophosphate are natural substrates of TNAP. Bone
osteopontin from TNAP knockout mice is highly phosphorylated, whereas
osteopontin from TNAP knockout mice expressing human TNAP is de-phosphorylated, similar to that in wild type mice, indicating that
osteopontin is also a natural substrate of TNAP and that phosphorylated
osteopontin contributes the impaired bone mineralization in TNAP knockout mice. Conditional TNAP knockout mice and TNAP mutants produced by ENU (
N-ethyl-N-nitrosourea) mutagenesis show milder
hypophosphatasia and are expected to be useful models of
adult hypophosphatasia.