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From The Burnham Institute,* La Jolla; and the Veteran’s Affairs Medical Center/University of California at San Diego, San Diego, California
Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyzes the mineralization inhibitor inorganic pyrophosphate (PPi). Deletion of the TNAP gene (Akp2) in mice results in hypophosphatasia characterized by elevated levels of PPi and poorly mineralized bones, which are rescued by deletion of nucleotide pyrophosphatase phosphodiesterase 1 (NPP1) that generates PPi. Mice deficient in NPP1 (Enpp1-/-), or defective in the PPi channeling function of ANK (ank/ank), have decreased levels of extracellular PPi and are hypermineralized. Given the similarity in function between ANK and NPP1 we crossbred Akp2-/- mice to ank/ank mice and found a partial normalization of the mineralization phenotypes and PPi levels. Examination of Enpp1-/- and ank/ank mice revealed that Enpp1-/- mice have a more severe hypermineralized phenotype than ank/ank mice and that NPP1 but not ANK localizes to matrix vesicles, suggesting that failure of ANK deficiency to correct hypomineralization in Akp2-/- mice reflects the lack of ANK activity in the matrix vesicle compartment. We also found that the mineralization inhibitor osteopontin (OPN) was increased in Akp2-/-, and decreased in ank/ank mice. PPi and OPN levels were normalized in [Akp2-/-; Enpp1-/-] and [Akp2-/-; ank/ank] mice, at both the mRNA level and in serum. Wild-type osteoblasts treated with PPi showed an increase in OPN, and a decrease in Enpp1 and Ank expression. Thus TNAP, NPP1, and ANK coordinately regulate PPi and OPN levels. The hypomineralization observed in Akp2-/- mice arises from the combined inhibitory effects of PPi and OPN. In contrast, NPP1 or ANK deficiencies cause a decrease in the PPi and OPN pools that leads to hypermineralization.
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