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

• Hypophosphatasia is an inborn error of metabolism characterized by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) and skeletal disease due to impaired mineralization of cartilage and bone matrix [10].
• A new lymphocyte surface antigen (Ly-m31) controlled by a gene closely linked to the Akp-2 locus on mouse chromosome 4 [11].
• One exception is a mesometrially located marginal zone of the decidua, which continues to express the TNAP gene until day 12 and the active protein until at least day 16 [12].
• Subsequently, the effect of FGF2 treatment on expression of PC-1, ANK, and TNAP in the calvarial osteoblastic cell line, MC3T3E1(C4), was investigated [13].
• A mouse embryonic stem cell line, frozen sections of long bones, alkaline phosphatase extracted from mouse bone, and serum were used as the source of TNAP for individual assays [14].

Associations of Akp2 with chemical compounds

• Phosphoethanolamine, inorganic pyrophosphate, and pyridoxal 5'-phosphate are putative natural substrates for TNSALP and all were increased endogenously in the knock-out mice [10].
• Observations in TNAP-KO mice, which analyzed the role of this enzyme in osteogenesis, had suggested that TNAP might be involved in GABA neurotransmission [15].
• 1,3,5-Trinitro-2-acetyl pyrrole (TNAP) is a product derived from the reaction of 2-acetyl pyrrole with nitrite in the model of Maillard browning systems [3].
• Reaction of AP with nitrite produces two N-nitropyrrole compounds, 1-nitro-2-acetyl-pyrrole (NAP) and 1,3,5-trinitro-2-acetylpyrrole (TNAP), the chemical structures of which have been confirmed by spectral studies, including UV mass, nuclear magnetic resonance, infra-red and elemental analysis (EA) [4].

Regulatory relationships of Akp2

• Serum alkaline phosphatase activity is regulated by a chromosomal region containing the alkaline phosphatase 2 gene (Akp2) in C57BL/6J and DBA/2J mice [9].
• FGF2 specifically induced expression of PC-1 and ANK while inhibiting expression of TNAP, at both mRNA and protein levels [13].

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

• Northern blot analysis and reverse-transcriptase polymerase chain reaction amplification of RNA indicate that this AP activity results from the expression of the Akp-2 locus [17].
• RT-PCR analysis revealed that the mRNA of the TNSALP gene was highly stimulated [18].
• After treatment by Pi starvation for 3 days, there was a 2-fold increase in the specific activity of TNSALP [18].
• Antibodies 314 and 315 reacted strongly with mouse TNAP in Western blots, while all other antibodies were negative [14].
• Enzyme immunoassays indicated that MAb 333 was also able to bind to serum TNAP [14].

References