OSTEOCALCIN SYNTHESIS AND CATABOLISM IN VIVO AND IN VITR

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Osteocalcin is a small protein comprising 20% of the noncollagenous protein in the extracellular matrix of bone. Current studies indicate that it is derived from higher molecular weight precursors and that its synthesis and processing is regulated by 1,25(OH)2D3. It may play a role in regulating hydroxylapatite crystal growth and recruiting osteoclasts to sites of bone resorption. Although investigations into the structure and properties of osteocalcin have progressed in the past several years, many questions remain regarding its biosynthesis and catabolism. In an effort to answer these questions we intend to: 1) Identify specific precursors of osteocalcin and study the effect of calcitropic hormones on synthesis and processing using rat and human bone cells in culture. 2) Identify specific fragments of osteocalcin that are produced during bone resorption using an organ culture system of devitalized bone and human peripheral monocytes. While osteocalcin is found predominantly in bone, traces occur in serum and levels determined by radioimmunoassay correlate with the rate of bone formation. In order to develop serum osteocalcin as a diagnostic marker for metabolic bone disease, we will: 1) Establish normal values based on age, sex, hormonal status, diet, and activity. 2) Study the relationship between serum osteocalcin and other indices of bone metabolism including mineral levels, alkaline phosphatase, urinary hydroxyproline, calcitropic hormones, and direct histomorphometric measurements. These parameters will be assessed in normal individuals and those with bone disorders. During osteoclastic bone resorption, fragments of osteocalcin may be secreted into the circulation. We will produce monoclonal antibodies to synthetic and naturally occurring fragments of osteocalcin and test them in the clinical studies outlined above. Through these studies, we hope to improve the understanding of the biosynthesis and catabolism of osteocalcin and its role in calcium homeostasis and bone metabolism. We also hope to establish the measurements of osteocalcin and its fragments as important discriminatory parameters for the diagnosis of bone disorders.