Endocrine role of bone: recent and emerging perspectives beyond osteocalcin

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   Figure 1

   The endocrine role of bone: osteocalcin and beyond. Arrows: continuous, accepted; dashed, speculative; black, known interactions; green, indirect interactions; red, direct interactions; blue, osteokines. A feed-forward loop links insulin, bone resorption and osteocalcin activity. Insulin signalling in osteoblasts decreases the expression of Opg by decreasing the ratio of Opg (a RANKL decoy receptor) to RANKL, thus increasing bone resorption by osteoclasts. This osteoclastic bone resorption generates an acidic pH in the resorption lacunae necessary to decarboxylate osteocalcin stored in the bone extracellular matrix. Undercarboxylated osteocalcin (GLU13-OC) is released into the bloodstream, affecting glucose metabolism by binding to the osteocalcin receptor (GPRC6A), thus stimulating insulin secretion and β-cell proliferation in the pancreas and promoting insulin sensitivity in peripheral organs. In addition, GLU13-OC promotes male fertility by stimulating testosterone synthesis in Leydig cells of the testis through GPRC6A activation. OST-PTP acts as an inhibitor, dephosphorylating the IR and suppressing the levels of GLU13-OC. To complete this feed-forward loop, peripheral/central tissues (adrenal gland, adipose tissue and pancreas) can further indirectly regulate the release of GLU13-OCN into the peripheral circulation. New emerging evidence indicates that, in addition, NPP1 can indirectly inhibit GLU13-OCN release via OPG. Independently of OCN, osteoblast-specific proteins (PHOSPHO1, AMPK and GSK3β) can influence insulin secretion from β-cells, their functions and adiposity. Osteocyte-derived factors – osteokines – may also be implicated in the endocrine regulation of glucose metabolism (figure adapted from Rosen & Motyl (2010) and Ferron & Lacombe (2014)).
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   Figure 2

   GLUT transporter family. Dendrogram of the extended GLUT family highlighting GLUT receptor tissue distribution and cellular/subcellular expression. Additionally, the role of GLUT proteins in the maintenance of glucose homoeostasis is summarised, outlining the relevant glucose-responsive tissues and the associated GLUT receptors (newly reported GLUT receptors in bone are also highlighted; figure adapted from Joost & Thorens (2001) and Mueckler & Thorens (2013)). Potential similarities between GLUT3 and GLUT14 are indicated by a red line. The role of bone GLUT1 and GLUT4 in glucose homoeostasis is speculative and indicated by a red double-headed arrow. BBB, blood–brain barrier; BTB, blood–testis barrier; WAT, white adipose tissue; BAT, brown adipose tissue; SI, small intestine.

• © 2015 Society for Endocrinology