Karsenty G, Oury F. Regulation of male fertility by the bone-derived hormone osteocalcin. Mol Cell Endocrinol 2014;382(1):521-6. Regulation of male fertility by the bone-derived hormone osteocalcin
Traditionally, bone has been viewed as a relatively static tissue only fulfilling mechanical and scaffolding function. In the past decade however, this classical view of the bone has considerably evolved towards a more complex picture. It is now clear that the skeleton is not only a recipient for hormonal input but it is also an endocrine organ itself.
Through the secretion of an osteoblast-derived molecule, osteocalcin, the skeleton regulates glucose homeostasis and male reproductive functions. When undercarboxylated, osteocalcin acts following its binding to a G-coupled receptor, Gprc6a, on pancreatic beta cells to increase insulin secretion, on muscle and white adipose tissue to promote glucose homeostasis and on Leydig cells of the testis to favor testosterone biosynthesis.
More recently, it was also shown that osteocalcin acts via a pancreas-bone-testis axis that regulates, independently of and in parallel to the hypothalamus-pituitary-testis axis, male reproductive functions by promoting testosterone biosynthesis. Lastly, in trying to expand the biological relevance of osteocalcin from mouse to human, it was shown that Gprc6a is a potential new susceptibility locus for primary testicular failure in humans.
Altogether, these results shed new light on the importance of the endocrine role of the skeleton and also provide credence to the search for additional endocrine functions of this organ.
The Skeleton Is an Endocrine Organ
The endocrine regulation of energy metabolism and male reproduction by the bone is mediated by osteocalcin, an osteoblast-specific secreted molecule.
Osteocalcin regulates energy metabolism by increasing insulin secretion, favoring pancreatic-b-cell proliferation, and increasing insulin sensitivity in various tissues.
In addition, it promotes male reproductive function by stimulating testosterone synthesis in Leydig cells.
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Molecular Mode of Action of Osteocalcin in Regulating Testosterone Production
Osteocalcin has an unusual mode of activation that relies on the interplay between two specific bone cells: Osteoblasts and Osteoclasts.
The osteoblasts produce and secrete an inactive form of this molecule (carboxylated) that is stored in the extracellular bone matrix (ECM). The activity of the osteoclasts create resorption lacunae in the ECM inducing a low PH (4.5) which is necessary and sufficient to bio-activate osteocalcin by promoting its undercarboxylation.
The mechanism by which osteocalcin is activated is regulated in osteoblasts by insulin signaling, which inhibits the expression in osteoblasts of the gene encoding osteoprotegerin (Opg), which hampers osteoclast differentiation.
Following its binding to Gprc6a expressed in Leydig cells, osteocalcin favors cAMP production that leads to the activation of the transcription factor CREB (cAMP response element binding). CREB activates the expression of several genes encoding the enzymes that are necessary for testosterone biosynthesis, such as StAR, Cyp11a, 3b-HSD and Cyp17.
Steroidogenic acute regulatory protein (StAR) is crucial for transport of cholesterol to mitochondria where biosynthesis of steroids is initiated. Cyp11a encodes the cholesterol side-chain cleavage enzyme (P450scc) that catalyzes the first and rate-limiting step, which converts cholesterol to pregnenolone. 3b-HSD and Cyp17 encode two enzymes required during the conversion of pregnenolone to testosterone.
Testosterone is a sex steroid hormone require for many aspects of testicular functions, such as germ cell survival and spermatogenesis.
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Osteocalcin-Stimulated Testosterone Biosynthesis Is Positively Regulated By Insulin Signaling In Osteoblasts
Insulin signaling in osteoblasts stimulates the bioactivation of osteocalcin.
In a feedback loop control, undercarboxylated active osteocalcin then stimulates insulin secretion by the b-cells of the pancreatic islets, promotes insulin sensitivity in peripheral organs and favors testosterone biosynthesis in Leydig cells of the testis.
Testosterone in turn favors bone growth, maintenance and maturation.
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