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

被引:94
作者
Anderson, HC
Harmey, D
Camacho, NP
Garimella, R
Sipe, JB
Tague, S
Bi, XH
Johnson, K
Terkeltaub, R
Millán, JL
机构
[1] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66160 USA
[2] Hosp Special Surg, New York, NY 10021 USA
[3] Burnham Inst, La Jolla, CA 92037 USA
[4] Univ Calif San Diego, Vet Adm Med Ctr, San Diego, CA 92103 USA
关键词
D O I
10.1016/S0002-9440(10)62481-9
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
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.
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页码:1711 / 1720
页数:10
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