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Osteopontin Deficiency Suppresses High Phosphate Load-Induced Bone Loss via Specific Modulation of Osteoclasts

Department of Molecular Pharmacology (Y.K., K.T., K.H., R.S., A.N., M.N.), Tokyo Medical and Dental University, Tokyo 101-0062, Japan; Department of Nutritional Sciences (S.R.R., D.T.D.), Rutgers University, Piscataway, New Jersey 08901; Department of Obstetrics and Gynecology (T.Y., Y.T.), University of Tokyo, Tokyo 113-8655, Japan; 21st Century Center of Excellence (COE) Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone (M.N.); Hard Tissue Genome Research Center (M.N.) and Integrated Action Initiative in Japan Society for the Promotion of Science Core to Core Program (M.N.)

Address all correspondence and requests for reprints to: Masaki Noda, Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 3-10 Kanda-Surugadai, 2-chome, Chiyoda-ku, Tokyo 101-0062, Japan. E-mail: noda.mph{at}mri.tmd.ac.jp.

Phosphate (Pi) plays a critical role in the maintenance of mineralized tissues and signaling in the intracellular environment. Although extracellular phosphate concentration is maintained at fixed levels, physiological machineries involved in phosphate homeostasis in bone, which is the largest phosphate storage site, have not yet been fully elucidated. Here we examined the role of osteopontin (OPN) in a high-Pi diet load-induced bone loss. A high-Pi diet significantly reduced bone mineral density as well as bone mass in wild type. In contrast, OPN deficiency totally prevented reduction in bone mineral density and bone mass. Analyses of bone turnover-related components revealed that bone formation parameters (bone formation rate and mineral apposition rate) were enhanced by high-Pi diet load similarly in wild-type and OPN-deficient mice. In sharp contrast, bone resorption parameters (osteoclast number and osteoclast surface) were enhanced by high-Pi diet load in wild type but not at all in OPN-deficient mice. Bone marrow cell cultures revealed no major effects of OPN deficiency on high-Pi diet modulation of mineralized nodule formation in culture. On the other hand, tartrate-resistant acid phosphatase-positive multinucleated cell development in cultures were enhanced by high-Pi diet load in wild-type cells, but such effects of high Pi-diet were totally abolished in the absence of OPN. These data indicated that OPN is needed for osteoclastic activity to resorb bone on high phosphate loading.

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