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Gene Review

Alpl  -  alkaline phosphatase, liver/bone/kidney

Mus musculus

Synonyms: AP-TNAP, APTNAP, Akp-2, Akp2, Alkaline phosphatase 2, ...
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Disease relevance of Akp2

  • Deletion of the TNAP gene (Akp2) in mice results in hypophosphatasia characterized by elevated levels of PP(i) and poorly mineralized bones, which are rescued by deletion of nucleotide pyrophosphatase phosphodiesterase 1 (NPP1) that generates PP(i) [1].
  • INTRODUCTION: Akp2(-/-) display mineralization deficiencies characterized by rickets/osteomalacia [2].
  • Experiments are performed to investigate the effects of TNAP on the hepatic toxicity in mouse [3].
  • NAP and TNAP are moderately mutagenic to the Salmonella strains TA98 and TA100 in the absence of a mammalian activation system and are markedly cytotoxic to mouse C3H10T1/2 cells [4].

High impact information on Akp2

  • ECM mineralization occurs only in bone because of the exclusive coexpression in osteoblasts of Type I collagen and Tnap, an enzyme that cleaves pyrophosphate [5].
  • Each allele of Akp2 and Enpp1 has a measurable influence on mineralization status in vivo [6].
  • The presence of skeletal hypomineralization was confirmed in mice lacking the gene for bone alkaline phosphatase, ie, the tissue-non-specific isozyme of alkaline phosphatase (TNAP) [7].
  • Alizarin red staining, microcomputerized tomography (micro CT), and FTIR imaging spectroscopy (FT-IRIS) confirmed a significant overall decrease of mineral density in the cartilage and bone matrix of TNAP-deficient mice [7].
  • High resolution TEM indicated that mineral crystals were initiated, as is normal, within matrix vesicles (MVs) of the growth plate and bone of TNAP-deficient mice [7].

Chemical compound and disease context of Akp2

  • However, these double knockout mice do not display corrected ePP(i) levels, and we conclude that regulation of hydroxyapatite deposition requires the coordinated actions of both PP(i) and OPN and that the hypophosphatasia phenotype in Akp2(-/-) mice results from the combined inhibitory action of increased levels of both ePP(i) and OPN [2].

Biological context of Akp2

  • Here, we show the respective correction of bone mineralization abnormalities in knockout mice null for both the TNAP (Akp2) and PC-1 (Enpp1) genes [6].
  • Elevated skeletal osteopontin levels contribute to the hypophosphatasia phenotype in Akp2(-/-) mice [2].
  • Tissue nonspecific alkaline phosphatase (TNAP), the product of the Akp2 locus, is expressed in mouse primordial germ cells (PGC) for an extensive period during embryogenesis [8].
  • The Akp2 gene, which encodes the major serum AP isozyme, falls within this QTL region at 70.2 cM where the LOD score reached 13.2 (LOD significance level set at 4.3) [9].
  • A variety of sequence polymorphisms in this chromosomal region could be responsible for the differences in serum AP activity; the Akp2 gene, however, with several known amino acid substitutions between protein sequences of the B6 and D2 strains, is a leading candidate [9].

Anatomical context of Akp2


Associations of Akp2 with chemical compounds


Regulatory relationships of Akp2


Other interactions of Akp2

  • Comparison with previously reported strain distribution patterns shows that the gene encoding the mouse Na+/H+ exchanger maps to distal mouse Chromosome 4, between Lck and Akp-2 [16].

Analytical, diagnostic and therapeutic context of Akp2


  1. Concerted regulation of inorganic pyrophosphate and osteopontin by akp2, enpp1, and ank: an integrated model of the pathogenesis of mineralization disorders. Harmey, D., Hessle, L., Narisawa, S., Johnson, K.A., Terkeltaub, R., Millán, J.L. Am. J. Pathol. (2004) [Pubmed]
  2. Elevated skeletal osteopontin levels contribute to the hypophosphatasia phenotype in Akp2(-/-) mice. Harmey, D., Johnson, K.A., Zelken, J., Camacho, N.P., Hoylaerts, M.F., Noda, M., Terkeltaub, R., Millán, J.L. J. Bone Miner. Res. (2006) [Pubmed]
  3. Hepatotoxicity of 1,3,5-trinitro-2-acetyl pyrrole derived from nitrosation of Maillard reaction product in BALB/C mouse. Lin, Y.L., Tseng, T.H., Hsu, J.D., Chu, C.Y., Wang, C.J. Toxicol. Lett. (1996) [Pubmed]
  4. Mutagenicity and cytotoxicity of nitropyrrole compounds derived from the reaction of 2-acetyl pyrrole with nitrite. Wang, C.J., Lin, Y.L., Lin, J.K. Food Chem. Toxicol. (1994) [Pubmed]
  5. Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone. Murshed, M., Harmey, D., Millán, J.L., McKee, M.D., Karsenty, G. Genes Dev. (2005) [Pubmed]
  6. Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization. Hessle, L., Johnson, K.A., Anderson, H.C., Narisawa, S., Sali, A., Goding, J.W., Terkeltaub, R., Millan, J.L. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  7. Impaired calcification around matrix vesicles of growth plate and bone in alkaline phosphatase-deficient mice. Anderson, H.C., Sipe, J.B., Hessle, L., Dhanyamraju, R., Atti, E., Camacho, N.P., Millán, J.L., Dhamyamraju, R. Am. J. Pathol. (2004) [Pubmed]
  8. Purification of primordial germ cells from TNAPbeta-geo mouse embryos using FACS-gal. Abe, K., Hashiyama, M., Macgregor, G., Yamamura, K. Dev. Biol. (1996) [Pubmed]
  9. Serum alkaline phosphatase activity is regulated by a chromosomal region containing the alkaline phosphatase 2 gene (Akp2) in C57BL/6J and DBA/2J mice. Foreman, J.E., Blizard, D.A., Gerhard, G., Mack, H.A., Lang, D.H., Van Nimwegen, K.L., Vogler, G.P., Stout, J.T., Shihabi, Z.K., Griffith, J.W., Lakoski, J.M., McClearn, G.E., Vandenbergh, D.J. Physiol. Genomics (2005) [Pubmed]
  10. Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia. Fedde, K.N., Blair, L., Silverstein, J., Coburn, S.P., Ryan, L.M., Weinstein, R.S., Waymire, K., Narisawa, S., Millán, J.L., MacGregor, G.R., Whyte, M.P. J. Bone Miner. Res. (1999) [Pubmed]
  11. A new lymphocyte surface antigen (Ly-m31) controlled by a gene closely linked to the Akp-2 locus on mouse chromosome 4. Tada, N., Kimura, S., Liu-Lam, Y., Hämmerling, U. Immunogenetics (1984) [Pubmed]
  12. Changes in the pattern of expression of alkaline phosphatase in the mouse uterus and placenta during gestation. Johansson, S., Wide, M. Anat. Embryol. (1994) [Pubmed]
  13. FGF2 alters expression of the pyrophosphate/phosphate regulating proteins, PC-1, ANK and TNAP, in the calvarial osteoblastic cell line, MC3T3E1(C4). Hatch, N.E., Nociti, F., Swanson, E., Bothwell, M., Somerman, M. Connect. Tissue Res. (2005) [Pubmed]
  14. Conserved epitopes in human and mouse tissue-nonspecific alkaline phosphatase. Second report of the ISOBM TD-9 workshop. Narisawa, S., Harmey, D., Magnusson, P., Millán, J.L. Tumour Biol. (2005) [Pubmed]
  15. Areal and subcellular localization of the ubiquitous alkaline phosphatase in the primate cerebral cortex: evidence for a role in neurotransmission. Fonta, C., Négyessy, L., Renaud, L., Barone, P. Cereb. Cortex (2004) [Pubmed]
  16. Localization of the mouse Na+/H+ exchanger gene on distal chromosome 4. Morahan, G., Rakar, S. Genomics (1993) [Pubmed]
  17. Stage-specific expression of alkaline phosphatase during neural development in the mouse. Narisawa, S., Hasegawa, H., Watanabe, K., Millán, J.L. Dev. Dyn. (1994) [Pubmed]
  18. Phosphate depletion enhances tissue-nonspecific alkaline phosphatase gene expression in a cultured mouse marrow stromal cell line ST2. Goseki-Sone, M., Yamada, A., Asahi, K., Hirota, A., Ezawa, I., Iimura, T. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
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