Sustained osteomalacia of long bones despite major improvement in other hypophosphatasia-related mineral deficits in tissue nonspecific alkaline phosphatase/nucleoticle pyrophosphatase phosphodiesterase 1 double-deficient mice
Sustained osteomalacia of long bones despite major improvement in other hypophosphatasia-related mineral deficits in tissue nonspecific alkaline phosphatase/nucleoticle pyrophosphatase phosphodiesterase 1 double-deficient mice
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DOI：
10.1016/s0002-9440(10)62481-9
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发表时间：
2005-06-01
影响因子：
6
通讯作者：
Millán, JL
中科院分区：
文献类型：
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作者：
Anderson, HC;Harmey, D;Millán, JL
我们以前已经表明，组织非特异性碱性磷酸酶（TNAP）缺陷（Akp 2（-/-））hypophosphatasia小鼠的颅骨和椎骨的矿化不足的缺陷是拯救的同时删除Enpp 1基因，它编码核苷酸焦磷酸酶磷酸二酯酶1（NPP 1）。相反，在[Akp 2（-/-）; Enpp 1（-/-）]双敲除小鼠中，Enpp（-/-）小鼠典型的脊椎骨突中的骨化过度得到纠正。在这里，我们已经检查了Akp 2（-/-），Enpp 1（-/-），和[Akp 2（-/-）; Enpp 1-（/-）]小鼠的appropriate骨骼，以确定在这些骨骼部位提供的救援程度。茜素红和阿尔新蓝对野生型、Akp 2（-/-）和[Akp 2（-/-）; Enpp 1（-/-）]小鼠骨骼的整体分析显示，尽管双敲除小鼠的颅骨和椎骨在矿物质沉积方面正常化，但股骨和胫骨没有。使用几种不同的方法，我们发现不仅在Akp 2（-/-）中，而且在Enpp 1（-/-）和[Akp 2（-/-）; Enpp 1（-/-）]股骨和胫骨中的矿化减少。对颅骨和骨髓来源的成骨细胞体外矿化结节形成的分析显示，与野生型细胞相比，Enpp 1（-/-）颅骨成骨细胞的矿物质沉积增加，但Enpp 1（-/-）长骨髓来源的成骨细胞的矿物质沉积减少。因此，Akp 2（-/-）小鼠的骨软化和Enpp 1（-/-）小鼠的长骨的低矿化表型不能通过同时缺失TNAP和NPP 1功能来挽救。
We have shown previously that the hypomineralization defects of the calvarium and vertebrae of tissue nonspecific alkaline phosphatase (TNAP)-deficient (Akp2(-/-)) hypophosphatasia mice are rescued by simultaneous deletion of the Enpp1 gene, which encodes nucleotide pyrophosphatase phosphodiesterase 1 (NPP1). Conversely, the hyperossification in the vertebral apophyses typical of Enpp(-/-) mice is corrected in [Akp2(-/-); Enpp1(-/-)] double-knockout mice. Here we have examined the appendicular skeletons of Akp2(-/-), Enpp1(-/-), and [Akp2(-/-);Enpp1-(/-)] mice to ascertain the degree of rescue afforded at these skeletal sites. Alizarin red and Alcian blue whole mount analysis of the skeletons from wild-type, Akp2(-/-), and [Akp2(-/-); Enpp1(-/-)] mice revealed that although calvarium and vertebrae of double-knockout mice were normalized with respect to mineral deposition, the femur and tibia were not. Using several different methodologies, we found reduced mineralization not only in Akp2(-/-) but also in Enpp1(-/-) and [Akp2(-/-); Enpp1(-/-)] femurs and tibias. Analysis of calvarial- and bone marrow-derived osteoblasts for mineralized nodule formation in vitro showed increased mineral deposition by Enpp1(-/-) calvarial osteoblasts but decreased mineral deposition by Enpp1(-/-) long bone marrow-derived osteoblasts in comparison to wild-type cells. Thus, the osteomalacia of Akp2(-/-) mice and the hypomineralized phenotype of the long bones of Enpp1(-/-) mice are not rescued by simultaneous deletion of TNAP and NPP1 functions.