Elsevier

Bone

Volume 82, January 2016, Pages 42-49
Bone

Review
New insights into the biology of osteocalcin

https://doi.org/10.1016/j.bone.2015.05.046Get rights and content

Highlights

  • Osteocalcin is a secreted factor influencing matrix mineralization and global metabolism.

  • Osteocalcin regulates glucose metabolism via a bone–pancreas endocrine loop.

  • New data suggests an additional role in cognition and male fertility.

  • Clinical studies suggest a more complex role for osteocalcin in human metabolism.

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.

Introduction

Osteoblasts are specialized mesenchymal cells that are primarily responsible for the synthesis and deposition of the mineralized, collagen-rich matrix that composes bone tissue. Over the last decade, studies have elaborated an expanded biological function for the osteoblast that is focused on the actions of bone-derived osteocalcin [1], [2]. Osteocalcin has routinely been used as a serum marker of osteoblastic bone formation and believed to act in the bone matrix to regulate mineralization, but new genetic and pharmacologic evidence now points to a hormonal role for the protein. These newly discovered actions link the energy demands of bone to global homeostasis [1], [3] and close a number of open endocrine loops associated with the impact of nutrient availability [4], [5], leptin [6], [7], adiponectin [8] and insulin [9] on skeletal metabolism. In this review, we summarize the current knowledge of osteocalcin function beginning with the initial suggestion that the protein inhibits mineralization and ending with evidence of the hormonal actions of osteocalcin in humans.

Section snippets

Structure and post-translational modifications of osteocalcin

Osteocalcin, also referred to as bone γ-carboxyglutamic acid (Gla) protein or BGP, is a 46–50 amino acid, 5.6 kDa secreted protein that is produced primarily by osteoblasts [10]. Smaller amounts are also produced by odontoblasts of the teeth and hypertrophic chondrocytes. The protein was first isolated by Price et al. [11], [12] from bovine and human bone and shown to represent the major fraction of Gla containing protein in bone. A second Gla-protein, isolated later by the same group, was

Role of osteocalcin in mineralization

Mature osteocalcin is secreted into the bone micro-environment and then undergoes a conformational change that aligns its calcium-binding Gla residues with the calcium ions in hydroxyapatite. This property was initially proposed as a mechanism that enables osteocalcin to initiate the formation of hydroxyapatite crystals [12]. However, subsequent work was more compatible with the notion that osteocalcin functions as an inhibitor of bone mineralization. In support of this idea, osteocalcin

Regulation of glucose metabolism by osteocalcin

Recent work from several groups has now clearly demonstrated a role for osteocalcin in the regulation of glucose metabolism. Studies by the Karsenty group showed that mice lacking osteocalcin accumulate body fat and exhibit dramatic impairments in glucose metabolism [3], [27]. Since osteocalcin is only produced by osteoblasts and can enter the circulation, Karsenty speculated that osteocalcin functions as a hormone in a manner analogous to leptin and adiponectin (Fig. 2). Osteocalcin's presence

Regulation of osteocalcin by insulin

The discovery of osteocalcin's role in regulating glucose metabolism was independently established by Fulzele et al. [9], [45] in the course of studies designed to examine insulin actions in osteoblasts. In these studies, mice lacking the insulin receptor specifically in osteoblasts (IRflox; Oc-Cre) developed a metabolic phenotype reminiscent of the osteocalcin null mice described by the Karsenty group [3]. IR knockout mice accumulated body fat and exhibited hyperglycemia with reductions in

A role for osteocalcin in fertility and cognition

The continued examination of the osteocalcin null mice by Karsenty and Oury [60] led to the description of two additional hormonal functions for undercarboxylated osteocalcin. First, osteocalcin null mice were noted to be poor breeders and to produce litters of significantly smaller numbers of pups than wild-type counterparts. This observation led Oury and colleagues [61] to postulate that undercarboxylated osteocalcin acts to regulate fertility and possibly the production of sex steroid

Gprc6a: an osteocalcin receptor

The demonstration of specific functions for circulating undercarboxylated osteocalcin prompted studies to identify its receptor in target tissues. Gprc6a, a G protein coupled receptor with no previously known function, is expressed by a wide variety of cell types including those found to respond to circulating osteocalcin [66], [67], and is activated by a number of unrelated ligands including cations, like calcium and zinc, and amino acids such as l-Arg and l-Lys [68], [69]. It is believed that

Evidence of an endocrine function for osteocalcin in humans

Since the initial discovery that osteocalcin impacts metabolism in the mouse, a number of studies have attempted to address the function of osteocalcin in humans. To date, the vast majority of studies have used a cross-sectional design to examine the association of circulating levels of total and/or undercarboxylated osteocalcin with altered glucose metabolism. These studies indicate that the levels of osteocalcin are negatively correlated with fasting glucose, fasting insulin, HOMA-IR (a

Perspective

The studies reviewed herein on the unexpected functions of osteocalcin underscore a paradigm shift in our understanding of skeletal physiology. The notion that bone is primarily a hormone-responsive tissue should now be replaced by one in which bone actively communicates with other organ systems and coordinates mineral ion homeostasis with overall energy balance. Clearly, osteocalcin can now be viewed as a bone-derived factor that influences glucose metabolism, reproduction and cognition

Conflicts of interest

None.

Acknowledgments

T.L. Clemens is supported by a Merit Review grant (BX001234) and is the recipient of a Research Career Scientist Award from the Veterans Administration. R.C. Riddle is supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH (DK099134).

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