Inactivation of two mouse alkaline phosphatase genes and establishment of a model of infantile hypophosphatasia

Abstract

We report the inactivation, via homologous recombination, of two of the three active mouse alkaline phosphatase genes, i.e., embryonic (EAP) and tissue nonspecific (TNAP). Whereas expression of the EAP isozyme was abolished in all tissues that express EAP developmentally (such as the preimplantation embryo, thymus, and testis), the EAP knock‐out mice show no obvious phenotypic abnormalities. They reproduce normally and give birth to live offspring, indicating the nonessential role of EAP during embryonic development. Mice deficient in the TNAP gene mimic a severe form of hypophosphatasia. These TNAP −/− mice are growth impaired, develop epileptic seizures and apnea, and die before weaning. Examination of the tissues indicates abnormal bone mineralization and morphological changes in the osteoblasts, aberrant development of the lumbar nerve roots, disturbances in intestinal physiology, increased apoptosis in the thymus, and abnormal spleens. Our results indicate that, in the mouse, TNAP appears not to be essential for the initial events leading to bone mineral deposition but that TNAP seems to play a role in the maintenance of this process after birth. The other phenotypic manifestations may be a consequence of the lack of TNAP in the developing neural tube between stages E8.5 and E13.5 of embryogenesis. We hypothesize that the autonomic nervous system is compromised in these TNAP −/− mice. Dev. Dyn. 208:432–446, 1997. © 1997 Wiley‐Liss, Inc.

Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization

“…The generation and characterization of the Akp2 KO mice has been reported (22,23). These Akp2 KO mice were hybrids of C57BL͞6 ϫ 129͞J mouse strains.…”

Cellular function and molecular structure of ecto-nucleotidases

“…Accordingly, mutations in the TNAP gene that cause impairment or loss of functional activity lead to hypophosphatasia in humans [486,487]. Similarly, TNAP knockout mice (Akp2−/−) accumulate extracellular PP i , reveal hypomineralization [488][489][490][491], and can serve as a model for the infantile form of hypophosphatasia [492]. The defect can be eliminated by subcutaneous injections of soluble TNAP targeted to mineralizing tissue [493,494] or by lentiviral application of a bone-targeted form of TNAP [495].…”

Entpd5 is essential for skeletal mineralization and regulates phosphate homeostasis in zebrafish

“…For example, deficiency in the ENPP1 gene can result in pathological soft-tissue mineralization, particularly in arteries (10,11). On the other hand, hypophosphatemia leads to decreased mineralization of skeletal tissues, as evidenced by genetic studies in which PHOSPHO1, PHEX (phosphate regulating gene with homologies to endopeptidases on the X chromosome), or TNAP function is diminished (4,12,13).…”