ReviewNew insights into the biology of osteocalcin☆
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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This article is part of a Special Issue entitled Bone and diabetes.