concept

Osteocalcin

Osteocalcin (OC), a 49-amino acid calcium-binding peptide secreted by mature osteoblasts, is the most abundant non-collagen protein found in bone [17,22]. Most OC secreted by osteoblasts is incorporated into the organic matrix that will later ossify into bone, however, a small fraction is secreted into the circulation. For this reason, OC is widely considered a bone formation marker and OC concentration correlates with direct measurement of bone formation [101]. However, OC incorporated into the organic bone matrix can be liberated during osteoclastic bone resorption. Vitamin K and 1,25-dihydroxyvitamin D are necessary for OC synthesis [102,103]. OC synthesis is induced by vitamin D. During synthesis, vitamin K dependent carboxylation occurs at specific glutamate residues, a post-translational modification enabling calcium binding. In the circulation, both carboxylated and non-carboxylated form of OC are present. Due to a short half-life, OC rapidly breaks down forming OC fragments. Some have thought these fragments may be a potential indicator of bone metabolism. OC contains three glutamic acid residues at positions 13, 17, and 20 that undergo vitamin K-dependent μ-carboxylation which increases its affinity for hydroxyapatite [104]. Consistent with this vitamin K-dependent post-translational processing, treatment with vitamin K antagonists, such as warfarin, increases the relative amount of un- or under-carboxylated OC and can lower total serum OC [105]. A fraction of OC subsequently undergoes decarboxylation and only uncarboxylated OC is able to regulate glucose homeostasis [106]. Although there has been substantial interest in selective measurement of uncarboxylated OC, this has yet to be implemented clinically. While primarily thought of as a bone formation marker, OC can be liberated during resorption. Accordingly, the net effect remains unclear in various clinical situations. In addition, method differences, analyte stability and high degree of biologic variation all contribute to uncertainty regarding the usefulness of OC in bone metabolism [107–109]. In summary, serum OC concentration provides important information about osteoblastic activity, rather than the severity of bone disorders. OC has recently reemerged as a molecule of intense interest in basic and translational skeletal biology owing to its newly discovered role as a bone-derived hormone influencing male fertility, glucose homeostasis, behavior due to direct effects in the central nervous system and muscle function in animal studies [110–112]. Due to its lability, samples for OC measurement have special collection and transportation requirements, i.e., samples should be refrigerated and processed within 4 h of collection. Hemolysis reduces OC by enhancing degradation. OC instability of OC is largely due to the labile 6-amino acid C-terminal sequence. Accordingly, immunoassays that target a more stable region, i.e., N-mid-OC fragment (amino acids 1–43), demonstrate substantially better analytical performance and clinical correlation [113].

Ref:
Lisa Di Medio, Maria Luisa Brandi, in Advances in Clinical Chemistry, 2021

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Added on May 25, 2022 by Barbara Van De Keer
Edited on Aug 6, 2022 by Barbara Van De Keer

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