The Endocrine Function of Osteocalcin Regulated by Bone Resorption: A Lesson from Reduced and Increased Bone Mass Diseases

Abstract

Bone is a peculiar tissue subjected to a continuous process of self-renewal essential to assure the integrity of the skeleton and to explicate the endocrine functions. The study of bone diseases characterized by increased or reduced bone mass due to osteoclast alterations has been essential to understand the great role played by osteocalcin in the endocrine functions of the skeleton. The ability of osteoclasts to regulate the decarboxylation of osteocalcin and to control glucose metabolism, male fertility, and cognitive functions was demonstrated by the use of animal models. In this review we described how diseases characterized by defective and increased bone resorption activity, as osteopetrosis and osteoporosis, were essential to understand the involvement of bone tissue in whole body physiology. To translate this knowledge into humans, recently published reports on patients were described, but further studies should be performed to confirm this complex hormonal regulation in humans.

Keywords: Osteocalcin; bone diseases; osteoclast.

Figure 1

Representation of osteocalcin post-translational modification. Post-translational carboxylation at three glutamic acid residues occurs by γ-glutamyl carboxylase that uses vitamin K, CO₂, and O₂ as cofactors. The carboxylated form of osteocalcin (Gla–Ocn) can be converted into a form with a lower grade of carboxylation (Glu–Ocn) by acidic pH.

Figure 2

Schematic representation of osteocalcin functions. Osteocalcin stored in the bone matrix in the carboxylated form (Gla–Ocn) is decarboxylated by acidic pH in the resorption lacuna. The undercarboxylated osteocalcin (Glu–Ocn) is released into the circulation and regulates muscle function, male fertility, and insulin secretion by its binding to the GPRC6A receptor while it controls cognitive functions through the GPR158 receptor.