Osteocalcin is the most abundant and thoroughly characterized of the non-collagenous proteins in bone. Although it is found predominantly in bone, nanomolar quantities can be measured in serum. Serum osteocalcin is generally regarded as a marker for bone formation but our studies imply that other factors, in addition to the rate of its synthesis, may affect osteocalcin concentrations in blood. These include: 1) the presence of immunoreactive fragments of osteocalcin in the circulation, 2) renal clearance of the protein or its fragments, and 3) the affinity of protein for hydroxyapatite. The clinical data cannot be fully appreciated without an understanding of the factors which determine osteocalcin's concentration in blood. In addition, there is a need for specific non-invasive markers of bone formation and resorption. Through these studies, we hope to aid in the interpretation of clinical data, and develop precise assays for use in the diagnosis and treatment of metabolic bone disorders. We propose to: I. Identify fragments of osteocalcin that are produced a) in vitro using isolated osteoclasts, and b) in vivo using perfused rat hindlimb. II. Study the clearance and catabolism of osteocalcin a) in perfused isolated liver, and b) in perfused isolated kidney. III. Produce monoclonal antibodies to specific regions of the protein. These include a) specific fragments that are produced during bone resorption, b) pro-osteocalcin peptide which is co- secreted during osteocalcin synthesis, and c) undercarboxylated osteocalcin which may be synthesized in normal individuals or in those with metabolic bone disease. IV. Develop a useful battery of assays for the evaluation of bone disorders. Concentrations of intact osteocalcin, both carboxylated and under carboxylated, specific fragments, and propeptide will be evaluated a) in normal individuals and b) in patients with metabolic bone diseases in relationship to standard biochemical and histological parameters.
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