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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 Pi Regulation via Pit1 Plays a Role in Bone Mineralization{triangledown}

Yuji Yoshiko,1,2* G. Antonio Candeliere,2 Norihiko Maeda,1 and Jane E. Aubin2*

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 (Pi) 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 NaPi 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 NaPi transporter Pit1 in osteoblast cultures. Among molecules expressed in osteoblasts and known to be related to Pi handling, stanniocalcin 1 was identified as an early response gene after foscarnet treatment; it was also regulated by extracellular Pi, and itself increased Pit1 accumulation in both osteoblast cultures and in vivo. These results provide new insights into the functional role of osteoblast autonomous Pi handling in normal bone mineralization and the abnormalities seen in skeletal tissue in hypophosphatemic disorders.

* Corresponding author. Mailing address for Jane E. Aubin: Department of Molecular and Medical Genetics, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, Canada M5S 1A8. Phone: (416) 978-4220. Fax: (416) 978-3954. E-mail: jane.aubin{at}utoronto.ca. Mailing address for Yuji Yoshiko: Department of Oral Growth and Developmental Biology, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. Phone and fax: 81-82-257-5620. E-mail: yyuji{at}hiroshima-u.ac.jp

{triangledown} Published ahead of print on 16 April 2007.

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.



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