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.
| Bailey, Stacyann; Karsenty, Gerard; Gundberg, Caren et al. (2017) Osteocalcin and osteopontin influence bone morphology and mechanical properties. Ann N Y Acad Sci 1409:79-84 |
| Rehder, Douglas S; Gundberg, Caren M; Booth, Sarah L et al. (2015) Gamma-carboxylation and fragmentation of osteocalcin in human serum defined by mass spectrometry. Mol Cell Proteomics 14:1546-55 |
| Booth, Sarah L; Centi, Amanda; Smith, Steven R et al. (2013) The role of osteocalcin in human glucose metabolism: marker or mediator? Nat Rev Endocrinol 9:43-55 |
| Kacena, Melissa A; Gundberg, Caren M; Kacena 3rd, William J et al. (2013) The effects of GATA-1 and NF-E2 deficiency on bone biomechanical, biochemical, and mineral properties. J Cell Physiol 228:1594-600 |
| Poundarik, Atharva A; Diab, Tamim; Sroga, Grazyna E et al. (2012) Dilatational band formation in bone. Proc Natl Acad Sci U S A 109:19178-83 |
| Gundberg, Caren M; Lian, Jane B; Booth, Sarah L (2012) Vitamin K-dependent carboxylation of osteocalcin: friend or foe? Adv Nutr 3:149-57 |
| Brownstein, Catherine A; Zhang, Junhui; Stillman, Althea et al. (2010) Increased bone volume and correction of HYP mouse hypophosphatemia in the Klotho/HYP mouse. Endocrinology 151:492-501 |
| Monir, A U; Gundberg, C M; Yagerman, S E et al. (2010) The effect of lead on bone mineral properties from female adult C57/BL6 mice. Bone 47:888-94 |
| Shea, M Kyla; Gundberg, Caren M; Meigs, James B et al. (2009) Gamma-carboxylation of osteocalcin and insulin resistance in older men and women. Am J Clin Nutr 90:1230-5 |
| Yoshida, Makiko; Jacques, Paul F; Meigs, James B et al. (2008) Effect of vitamin K supplementation on insulin resistance in older men and women. Diabetes Care 31:2092-6 |
Showing the most recent 10 out of 35 publications
