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J. Biol. Chem., Vol. 279, Issue 24, 25464-25473, June 11, 2004

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Bone Acidic Glycoprotein-75 Delineates the Extracellular Sites of Future Bone Sialoprotein Accumulation and Apatite Nucleation in Osteoblastic Cultures^*

Ronald J. Midura, Aimin Wang, Dinah Lovitch¶, Douglas Law||, Kimerly Powell, and Jeff P. Gorski¶

From the Department of Biomedical Engineering and the Orthopaedic Research Center, Lerner Research Institute, The Cleveland Clinic and Foundation, Cleveland, Ohio 44195, the ^¶Division of Biochemistry and Molecular Biology, School of Biological Sciences, and Department of Oral Biology, School of Dentistry, University of Missouri-Kansas City, Kansas City, Missouri 64108, and the ^||Division of Cell Biology and Biophysics, School of Biological Sciences, University of Missouri-Kansas City, Kansas City, Missouri 64110

Addition of an organophosphate source to UMR osteoblastic cultures activates a mineralization program in which BSP localizes to extracellular matrix sites where hydroxyapatite crystals are subsequently nucleated (Wang, A., Martin, J. A., Lembke, L. A., and Midura, R. J. (2000) J. Biol. Chem. 275, 11082–11091). This study identifies for the first time novel extracellular spherical structures, termed biomineralization foci (BMF), containing bone acidic glycoprotein-75 (BAG-75), bone sialoprotein (BSP), and alkaline phosphatase that are the exclusive sites of initial nucleation of hydroxyapatite crystals in the UMR model. Importantly, in the absence of added phosphate, UMR cultures after reaching confluency contain two size populations of morphologically identifiable BMF precursors enriched in BAG-75 (15–25 and 150–250 µm in diameter). The shape and size of the smaller population are similar to structures assembled in vitro through self-association of purified BAG-75 protein (Gorski, J. P., Kremer, E. A., Chen, Y., Ryan, S., Fullenkamp, C., Delviscio, J., Jensen, K., and McKee, M. D. (1997) J. Cell. Biochem. 64, 547–564). After organophosphate addition, BSP accumulates within these BAG-75-containing BMF precursors, with hydroxyapatite crystal nucleation occurring subsequently. In summary, BAG-75 is the earliest detectable biomarker that accurately predicts the extracellular sites of de novo biomineralization in UMR cultures. We hypothesize that BAG-75 may perform a key structural role in the assembly of BMF precursors and the recruitment of other proteins such as alkaline phosphatase and BSP. Furthermore, we propose a hypothetical mechanism in which BAG-75 and BSP function actively in nucleation of apatite within BMF.

Received for publication, November 12, 2003 , and in revised form, March 5, 2004.

^* This work was supported by National Institutes of Health Grant AR-45171 and The Lerner Research Institute of The Cleveland Clinic Foundation (to R. J. M.) and National Institutes of Health Grants DE-14619 and DE-11197 and the University of Missouri Research Board (to J. P. G). This work was presented in preliminary form at the 25th Annual Meeting of the American Society for Bone and Mineral Research, September 19–23, 2003, Minneapolis, MN (69). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. Biomedical Engineering, ND20, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-445-3212; Fax: 216-445-4383; E-mail: midura{at}bme.ri.ccf.org.

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