Osteocalcin Synthesis and Catabolism

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): Vitamin K is involved in the physiological activation of various proteins involved in hemostasis and bone and cartilage metabolism. Osteocalcin is a vitamin K-dependent Ca2+binding protein found in the organic matrix of bone and dentin. Circulating osteocalcin is a highly specific osteoblastic marker and it has been widely used for assessing bone turnover. The studies proposed here seek to verify new methods for the measurement of osteocalcin or its fragments as indicators of vitamin K status and bone turnover. These studies will evaluate: (1) the relationship between circulating levels of osteocalcin fragments and bone accretion and resorption via calcium kinetics; and (2) the effect of vitamin K intake on the profile of circulating forms of osteocalcin and their correlation with other measures of bone turnover. Although, the function of osteocalcin has not been precisely defined, studies in mice suggest that osteocalcin may play a role in bone remodeling. The proposed studies will (1) rescue the osteocalcin null mouse (OC-/-) with an uncarboxylated variant such that osteocalcin will not accumulate in bone but circulating levels will be elevated. The effects of 1,25(OH)2D3 and ovariectomy in wt, OC-/- and rescued animals will be evaluated by bone density, mineral content, bone turnover markers histomorphometric parameters and osteoclast development. Osteoclast and/or osteoblast progenitors will be evaluated in bone marrow cells.