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Genetically Modified Mice for Studying TNAP Function
1Sanford-Burnham Medical Research Institute, La Jolla, CA, USA, sonokon@sanfordburnham.org.
Abstract:
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.
Insights
Genetically modified mice lacking tissue-nonspecific alkaline phosphatase (TNAP) exhibit hypophosphatasia. Enzyme replacement therapy and transgenic models offer insights into TNAP function and disease treatment.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Genetically modified mice are crucial for studying gene function and modeling human diseases.
- Tissue-nonspecific alkaline phosphatase (TNAP) plays a vital role in biological processes.
- Dysfunction of TNAP is associated with hypophosphatasia, a metabolic bone disorder.
Purpose of the Study:
- To describe knockout and transgenic mouse models of TNAP.
- To investigate the function of TNAP using these mouse models.
- To explore potential therapeutic strategies for TNAP deficiency.
Main Methods:
- Generation and characterization of conventional, conditional, and ENU-mutagenized TNAP knockout mouse lines.
- Enzyme replacement therapy using recombinant human TNAP.
- Analysis of double knockout mice with related enzymes.
- Biochemical assays to identify TNAP substrates and assess protein phosphorylation.
Main Results:
- Conventional TNAP knockout mice display lethal epilepsy and impaired bone mineralization, resembling infantile hypophosphatasia.
- Recombinant human TNAP administration rescues the lethal phenotype and improves bone mineralization.
- Pyridoxal phosphate, inorganic pyrophosphate, and osteopontin identified as natural substrates of TNAP.
- Conditional knockout and ENU mutant mice model milder forms of hypophosphatasia, relevant to adult disease.
Conclusions:
- TNAP knockout mice are valuable models for studying hypophosphatasia and TNAP function.
- Enzyme replacement therapy with TNAP is a viable treatment for TNAP deficiency disorders.
- Identification of TNAP substrates deepens understanding of its role in bone mineralization and neurological function.
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