It has been proposed that bone phosphoproteins participate in the initiation and/or distribution of mineralization by providing a locus where the stereochemical orientation of Ca++ and phosphate is most favorable to the formation of hydroxyapatite crystals. Osteopontin is a bone phosphoprotein of about 60 to 70 kDa that contains several distinct domains, including a Gly-Arg-Gly-Asp-Ser cell surface receptor binding site, a poly Asp motif and several phosphate groups on Ser and/or Thr residues which are possibly involved in the binding of Ca++. Osteopontin is also expressed in kidney, hypertrophic chondrocytes and intestine; and its expression is controlled at the level of transcription by calcitropic hormones, transforming growth factors and phorbol esters. The actual function of osteopontin, however, in the various tissues where it is expressed remains to be determined. We have cloned to osteopontin gene from mouse and propose here to characterize this gene in order to identify the DNA sequences responsible for the control of its expression. We also propose to generate a set of transgenic mice to help determine the function of osteopontin in bone and other tissues where it is expressed. The gene expression studies in combination with the phenotypical analysis of transgenic mice will yield answers to a variety of questions on the role of osteopontin in bone mineralization and in the metabolism of Ca++ and phosphate. Furthermore, transgenic mice which are defective for the expression of osteopontin may provide an animal model for bone formation disorders in humans.
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