Concerted regulation of inorganic pyrophosphate and osteopontin by Akp2, Enpp1, and Ank -: An integrated model of the pathogenesis of mineralization disorders
Concerted regulation of inorganic pyrophosphate and osteopontin by Akp2, Enpp1, and Ank -: An integrated model of the pathogenesis of mineralization disorders
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DOI：
10.1016/s0002-9440(10)63208-7
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发表时间：
2004-04-01
影响因子：
6
通讯作者：
Millán, JL
中科院分区：
文献类型：
--
作者：
Harmey, D;Hessle, L;Millán, JL
组织非特异性碱性磷酸酶（TNAP）水解矿化抑制剂无机焦磷酸盐（PP）。小鼠中TNAP基因（Akp 2）的缺失导致以PPi水平升高和矿化不良为特征的低磷酸酯酶症，其通过产生PPi的核苷酸焦磷酸酶磷酸二酯酶1（NPP 1）的缺失来挽救。NFP 1（Enpp 1（-/-））缺陷或ANK（ank/ank）的PPi通道功能缺陷的小鼠，细胞外PP水平降低，并且矿化过度。鉴于ANK和NPP 1之间功能的相似性，我们将Akp 2（-/-）小鼠与ank/ank小鼠杂交，发现矿化表型和PP 1水平部分正常化。对Enpp 1（-/-）和ank/ank小鼠的检查显示，Enpp 1（-/-）小鼠比ank/ank小鼠具有更严重的高矿化表型，NPP 1而不是ANK定位于基质囊泡，这表明ANK缺乏未能纠正Akp 2（-/-）小鼠的低矿化，反映了基质囊泡室中ANK活性的缺乏。我们还发现，矿化抑制剂骨桥蛋白（OPN）在Akp 2（-/-）小鼠中增加，而在ank/ank小鼠中减少。在[Akp 2（-/-）Enpp 1（-/-）]和[Akp 2（-/-）ank/ank]小鼠中，PPi和OPN水平在mRNA水平和血清中均正常化。PPi处理的Wad型成骨细胞显示OPN增加，Enpp 1和Ank表达减少。因此，TNAP、NPP 1和ANK协同调节PPi和OPN水平。在Akp 2（-/-）小鼠中观察到的低矿化由PPi和OPN的组合抑制作用引起。相反，NPP 1或ANK缺乏导致PPi和OPN池减少，导致过度矿化。
Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyzes the mineralization inhibitor inorganic pyrophosphate (PP). 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 NFP1 (Enpp1(-/-)), or defective in the PPi channeling function of ANK (ank/ank), have decreased levels of extracellular PP, 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 PP, levels. Examination of Enpp1(-/-) and ank/ank mice revealed that Enpp1(-/-) mice have a more severe hyperinineralized 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. Wad-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.