Searching for additional endocrine functions of the skeleton: genetic approaches and implications for therapeutics

Abstract

Our knowledge of whole organism physiology has greatly advanced in the past decades through mouse genetics. In particular, genetic studies have revealed that most organs interact with one another through hormones to maintain normal physiological functions and the homeostasis of the entire organism. Remarkably, through these studies, many unexpected novel endocrine means to regulate physiological functions have been uncovered. The skeletal system is one example. In this article, we review a series of studies that over the years have identified bone as an endocrine organ. The mechanism of action, pathological relevance and therapeutic implications of the functions of the bone-derived hormone osteocalcin are discussed. In the last part of this review, we discuss the possibility that additional endocrine functions of the skeleton may exist.

Keywords:

• cognition and brain development
• glucose homeostasis
• osteoblast
• osteocalcin
• reproduction

Financial & competing interests disclosure

This work was supported by NIH grant R01AR045548 received by G Karsenty. This work was also supported by Columbia University Mandl Connective Tissue Research Fellowship received by J Wei. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Bone through osteocalcin, a hormone specifically produced by osteoblasts, exerts multiple endocrine functions.

• Cell-specific gain-of and loss-of function mouse genetic studies revealed that osteocalcin, favors glucose homeostasis by promoting pancreatic β-cell proliferation, insulin synthesis, secretion and sensitivity.

• Osteocalcin is active in its undercarboxylated form. By promoting bone resorption, insulin signaling in osteoblasts favors decarboxylation of osteocalcin, i.e., activation of this hormone.

• Osteocalcin favors male fertility by promoting Leydig cells maturation and testosterone production.

• Gprc6a, a GPCR, is a bonafide receptor of osteocalcin in mice and humans mediating osteocalcin functions in Leydig cells and pancreatic β-cells.

• Osteocalcin prevents anxiety and depression and promotes learning and memory by favoring neurogenesis prenatally and postnatally.

• Both clinical observations and mouse genetic studies suggest that osteocalcin is a significant contributor to the pathogenesis of diabetes and the metabolic side effects of chronic glucocorticoid therapy.

• Pharmacological studies have demonstrated that osteocalcin could be a potential treatment for metabolic diseases.

• Identification of additional functions of osteocalcin and novel bone-derived hormones will bring new insight in the development of therapeutic treatment of various systemic diseases, such as bone diseases, diabetes, infertility and cognitive diseases.