POSTTRANSLATIONAL MODIFICATION/STRUCTURE-FUNCTION OF BON

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DESCRIPTION: (Adapted from the Application). Non-collagenous extracellular matrix (ECM) glycosylated phosphoproteins, osteopontin (OPN) and bone sialoprotein (BSP), have been postulated to play significant roles in the formation, resorption and mineralization of bone, and sufficient evidence exists to suggest that these functions are in part regulated via post-translational modification of the proteins. However, a clear understanding of the regions/sites that contain phosphoryl/glycosyl moieties and the functions of these regions remain predominantly undefined. The coupling of the functions of these proteins with and their dependence on the state of phosphorylation indicates that the overall quality of the bone may vary as a function of aging due to perturbations in their phosphorylation, thus leading to bone-related disorders. Clearly the importance of bone ECM phosphoproteins is becoming increasingly apparent by the continuing additional members being discovered and the emerging interests of investigators in general fields of biological sciences studying ECM phosphoproteins and their role in cell-cell communication and cell-matrix interactions. These investigators have recently discovered two novel bone ECM proteins, osteometric (OMN) and osteocontin (OCN), with similar post-translational modifications as those of OPN and BSP. They will clone and express the novel phosphoproteins, OMN and OCN, in bacterial and in mammalian cells for post- translational modification studies, and studies on effects of OMN and OCN on osteoclast formation and osteoblast mineralization. Thus, one of the overall objectives of this proposal is to evaluate and define precisely the relationship between concentration, state and precise sites of phosphorylation of bone ECM phosphoproteins, OPN, BSP, OMN and OCN as a function of bone age and extent of biomineralization process. Hence, we will aim to define the mechanism(s) by which bone loss and perturbations in biomineralization may occur as a result of aging and hormonal deficiency and the role of glycosylated phosphoproteins, in particular the process of phosphorylation, in such events. The proposed studies herein will utilize the latest technologies and innovative approaches developed/pioneered in this laboratory to ascertain the effective and efficient execution of the work with important implications in bone biology. This research concerns the study of four proteins, the functions of which are likely to be of considerable importance in the regulation of skeletal turnover and function. As such, the results could, in the long term, lead to the development of new therapeutics, diagnostic reagents and devices for use in a number of diseases and conditions of major clinical and health economical impactosteoporosis, bone metastasis, fracture healing, etc.