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Bogan R.,Johns Hopkins University | Riddle R.C.,Johns Hopkins University | Riddle R.C.,Baltimore Veterans Administration Medical Center | Li Z.,Johns Hopkins University | And 7 more authors.
Journal of Bone and Mineral Research | Year: 2013

Osteogenesis imperfecta type VI (OI type VI) has recently be linked to a mutation in the SERPINF1 gene, which encodes pigment epithelium-derived factor (PEDF), a ubiquitously expressed protein originally described for its neurotrophic and antiangiogenic properties. In this study, we characterized the skeletal phenotype of a mouse with targeted disruption of Pedf. In normal mouse bone, Pedf was localized to osteoblasts and osteocytes. Micro-computed tomography (μCT) and quantitative bone histomorphometry in femurs of mature Pedf null mutants revealed reduced trabecular bone volume and the accumulation of unmineralized bone matrix. Fourier transform infrared microscopy (FTIR) indicated an increased mineral:matrix ratio in mutant bones, which were more brittle than controls. In vitro, osteoblasts from Pedf null mice exhibited enhanced mineral deposition as assessed by Alizarin Red staining and an increased mineral:matrix determined by FTIR analysis of calcified nodules. The findings in this mouse model mimic the principal structural and biochemical features of bone observed in humans with OI type VI and consequently provide a useful model with which to further investigate the role of PEDF in this bone disorder. Copyright © 2013 American Society for Bone and Mineral Research. Source

Boskey A.L.,Mineralized Tissue Research Laboratory | Boskey A.L.,Cornell University | Lukashova L.,Mineralized Tissue Research Laboratory | Spevak L.,Mineralized Tissue Research Laboratory | And 2 more authors.
Bone | Year: 2013

Mutations in the kidney NaPiIIa co-transporter are clinically associated with hypophosphatemia, hyperphosphaturia (phosphate wasting), hypercalcemia, nephrolithiasis and bone demineralization. The mouse lacking this co-transporter system was reported to recover its skeletal defects with age, but the "quality" of the bones was not considered. To assess changes in bone quality we examined both male and female NaPiIIa knockout (KO) mice at 1 and 7. months of age using micro-computed tomography (micro-CT) and Fourier transform infrared imaging (FTIRI). KO cancellous bones at both ages had greater bone volume fraction, trabecular thickness and lesser structure model index based on micro-CT values relative to age- and sex-matched wildtype animals. There was a sexual-dimorphism in the micro-CT parameters, with differences at 7. months seen principally in males. Cortical bone at 1. month showed an increase in bone volume fraction, but this was not seen at 7. months. Cortical thickness which was elevated in the male and female KO at 1. month was lower in the male KO at 7. months. FTIRI showed a reduced mineral and acid phosphate content in the male and female KO's bones at 1. month with no change in acid phosphate content at 7. months. Collagen maturity was reduced in KO cancellous bone at 1. month. The observed sexual dimorphism in the micro-CT data may be related to altered phosphate homeostasis, differences in animal growth rates and other factors. These data indicate that the bone quality of the KO mice at both ages differs from the normal and suggests that these bone quality differences may contribute to skeletal phenotype in humans with mutations in this co-transporter. © 2013 Elsevier Inc.. Source

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