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(American Journal of Pathology. 2005;166:1711-1720.)
© 2005 American Society for Investigative Pathology

Sustained Osteomalacia of Long Bones Despite Major Improvement in Other Hypophosphatasia-Related Mineral Deficits in Tissue Nonspecific Alkaline Phosphatase/Nucleotide Pyrophosphatase Phosphodiesterase 1 Double-Deficient Mice

H. Clarke Anderson^*, Dympna Harmey, Nancy P. Camacho, Rama Garimella^*, Joseph B. Sipe^*, Sarah Tague^*, Xiaohong Bi, Kristen Johnson, Robert Terkeltaub and José Luis Millán

From the University of Kansas Medical Center,^* Kansas City, Kansas; the Hospital for Special Surgery, New York, New York; the Burnham Institute, La Jolla, California; and the Veterans Administration Medical Center/University of California San Diego, San Diego, California

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 Enpp1^–/– 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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