New insights into the biology of osteocalcin

Abstract

Osteocalcin is among the most abundant proteins in bone and is produced exclusively by osteoblasts. Initially believed to be an inhibitor of bone mineralization, recent studies suggest a broader role for osteocalcin that extends to the regulation of whole body metabolism, reproduction, and cognition. Circulating undercarboxylated osteocalcin, which is regulated by insulin, acts in a feed-forward loop to increase β-cell proliferation as well as insulin production and secretion, while skeletal muscle and adipose tissue respond to osteocalcin by increasing their sensitivity to insulin. Osteocalcin also acts in the brain to increase neurotransmitter production and in the testes to stimulate testosterone production. At least one putative receptor for osteocalcin, Gprc6a, is expressed by adipose, skeletal muscle, and the Leydig cells of the testes and appears to mediate osteocalcin's effects in these tissues. In this review, we summarize these new discoveries, which suggest that the ability of osteocalcin to function both locally in bone and as a hormone depends on a novel post-translational mechanism that alters osteocalcin's affinity for the bone matrix and bioavailability. This article is part of a Special Issue entitled Bone and diabetes.

Keywords: Diabetes; Metabolism; Osteoblast; Osteocalcin.

Figure 1. Osteocalcin structure, translation, and processing

(A) The structure of osteocalcin is marked by three γ-carboxyglutamic acid residues and a disulfide bond. The human protein contains 49 amino acids with γ-carboxyglutamic acid residues at positions 17, 21, and 24 and a disulfide bond between cysteine residues at positions 23 and 29. The mouse protein is 3 amino acids shorter with γ-carboxyglutamic acid residues at positions 13, 17, and 20. (B) Osteocalcin is translated as a pre-pro-peptide. Following signal sequence cleavage the peptide translocates into the endoplasmic reticulum, where a disulfide bond forms. After processing in a potential protein convertase step, osteocalcin is γ-carboxylatedon three glutamic acid residues.

Figure 2. Hormonal effects of osteocalcin on whole body metabolism

In response to insulin, undercarboxylated osteocalcin is produced by the osteoblast or released from the bone matrix by the low pH of the osteoclast resorption pit and enters the circulation where it acts as a hormone. Osteocalcin produces a widespread increase in insulin sensitivity, which may be partially mediated by the increased production of adiponectin by adipose tissue. In the pancreas, osteocalcin causes an increase in β-cell proliferation as well as increased insulin production. Additional studies have suggested that osteoclacin acts in the brain to stimulate neurotransmitter production and in the testes to increase testosterone production.