title: 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.affiliation: Dept. of Pathology and Lab Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA. handerso@kumc.edu
authors.forename: H Clarke
authors.initials: HC
authors.lastname: Anderson
authors.forename: Dympna
authors.initials: D
authors.lastname: Harmey
authors.forename: Nancy P
authors.initials: NP
authors.lastname: Camacho
authors.forename: Rama
authors.initials: R
authors.lastname: Garimella
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Sipe
authors.forename: Sarah
authors.initials: S
authors.lastname: Tague
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Bi
authors.forename: Kristen
authors.initials: K
authors.lastname: Johnson
authors.forename: Robert
authors.initials: R
authors.lastname: Terkeltaub
authors.forename: José Luis
authors.initials: JL
authors.lastname: Millán
mesh_terms: D000469:Alkaline Phosphatase / Q000172:deficiency*; D000818:Animals; D015153:Blotting, Western; D002113:Calcification, Physiologic / Q000502:physiology*; D004195:Disease Models, Animal; D005269:Femur / Q000503:physiopathology / Q000648:ultrastructure; D007014:Hypophosphatasia / Q000150:complications / Q000503:physiopathology*; D007150:Immunohistochemistry; D007867:Leg Bones / Q000503:physiopathology* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism; D010018:Osteomalacia / Q000209:etiology / Q000503:physiopathology*; D010727:Phosphoric Diester Hydrolases / Q000172:deficiency*; D011755:Pyrophosphatases / Q000172:deficiency*; D012886:Skull / Q000473:pathology; D017550:Spectroscopy, Fourier Transform Infrared; D013977:Tibia / Q000503:physiopathology / Q000648:ultrastructure; D014057:Tomography, X-Ray Computed
chemical_list: D000469:Alkaline Phosphatase; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; C405782:nucleotide pyrophosphatase - phosphodiesterase I