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.

Abstract

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.

• Authors: H Clarke Anderson, Dympna Harmey, Nancy P Camacho, Rama Garimella, Joseph B Sipe, Sarah Tague, Xiaohong Bi, Kristen Johnson, Robert Terkeltaub, José Luis Millán
• Journal: The American journal of pathology (Am J Pathol) Vol. 166 Issue 6 Pg. 1711-20 (Jun 2005) ISSN: 0002-9440 [Print] United States
• PMID: 15920156 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Alkaline Phosphatase
• Phosphoric Diester Hydrolases
• Pyrophosphatases
• nucleotide pyrophosphatase - phosphodiesterase I

Topics

• Alkaline Phosphatase (deficiency)
• Animals
• Blotting, Western
• Calcification, Physiologic (physiology)
• Disease Models, Animal
• Femur (physiopathology, ultrastructure)
• Hypophosphatasia (complications, physiopathology)
• Immunohistochemistry
• Leg Bones (physiopathology, ultrastructure)
• Mice
• Mice, Knockout
• Osteoblasts (metabolism)
• Osteomalacia (etiology, physiopathology)
• Phosphoric Diester Hydrolases (deficiency)
• Pyrophosphatases (deficiency)
• Skull (pathology)
• Spectroscopy, Fourier Transform Infrared
• Tibia (physiopathology, ultrastructure)
• Tomography, X-Ray Computed