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Molecular and Cellular Biology, June 2007, p. 4465-4474, Vol. 27, No. 12
0270-7306/07/$08.00+0     doi:10.1128/MCB.00104-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Osteoblast Autonomous P_i Regulation via Pit1 Plays a Role in Bone Mineralization

Department of Oral Growth and Developmental Biology, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan,¹ Department of Molecular and Medical Genetics, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada²

Received 17 January 2007/ Returned for modification 1 March 2007/ Accepted 5 April 2007

The complex pathogenesis of mineralization defects seen in inherited and/or acquired hypophosphatemic disorders suggests that local inorganic phosphate (P_i) regulation by osteoblasts may be a rate-limiting step in physiological bone mineralization. To test whether an osteoblast autonomous phosphate regulatory system regulates mineralization, we manipulated well-established in vivo and in vitro models to study mineralization stages separately from cellular proliferation/differentiation stages of osteogenesis. Foscarnet, an inhibitor of NaP_i transport, blocked mineralization of osteoid formation in osteoblast cultures and local mineralization after injection over the calvariae of newborn rats. Mineralization was also down- and upregulated, respectively, with under- and overexpression of the type III NaP_i transporter Pit1 in osteoblast cultures. Among molecules expressed in osteoblasts and known to be related to P_i handling, stanniocalcin 1 was identified as an early response gene after foscarnet treatment; it was also regulated by extracellular P_i, and itself increased Pit1 accumulation in both osteoblast cultures and in vivo. These results provide new insights into the functional role of osteoblast autonomous P_i handling in normal bone mineralization and the abnormalities seen in skeletal tissue in hypophosphatemic disorders.

Published ahead of print on 16 April 2007.

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