REGULATION OF OSTEOCALCIN CONCENTRATIONS IN BLOOD

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Osteocalcin is an abundant calcium binding protein indigenous to the organic matrix of bone. Development of radioimmunoassays for osteocalcin revealed that it circulates in blood. Several studies have suggested that the measurement of serum osteocalcin may be of use in the evaluation and treatment of patients with metabolic bone disease. Serum osteocalcin is generally regarded as a marker of bone formation, but multiple factors may determine osteocalcin concentrations in blood. These include: bone cell synthesis and catabolism of the protein, regulation of osteocalcin affinity for hydroxyapatite, and clearance of the protein or its metabolic fragments by the kidney. Long term objectives are to a) provide a clear understanding of the factors which regulate osteocalcin concentration in blood, b) establish the function of the protein in bone, and c) develop precise biochemical assays for use in the diagnosis and treatment of metabolic bone disorders. The specific aims of this proposal are to: 1. investigate the qualitative and quantitative effects of chronic and acute administration of calcitropic hormones and minerals on circulating osteocalcin in normal and thyroparathyroidectomized rats. 2. determine if there are any acute changes in the binding affinity of osteocalcin to hydroxyapatite produced by alterations in local mineral concentrations. 3. study the relationship of serum osteocalcin to calcium flux in 45Ca prelabelled rats. 4. determine if there are alterations in the calcemic or phosphatemic response to calcitropic hormones in osteocalcin deficient rats. 5. study the regulation of the renal handling of osteocalcin in isolated perfused rat kidney. 6. examine the regulation of the catabolism of osteocalcin in perfused isolated rat hindquarters. 7. identify specific fragments of osteocalcin produced during bone resorption. 8. produce monoclonal antibodies to such fragments for use in clinical studies. 9. establish normal values of osteocalcin in human studies 10. evaluate relationships between osteocalcin and other biochemical and histological parameters of bone metabolism in normal individuals and those with metabolic bone disease.