Bone as an Endocrine Organ

Anyonya R. Guntur, PhD; Clifford J. Rosen, MD


Endocr Pract. 2012;18(5):758-762. 

In This Article

Osteocalcin and Its Role in Regulating Testosterone

Osteocalcin may also have another hormonal role, this time as a mediator of testosterone secretion. Osteocalcin was shown to induce testosterone production in Leydig cells of the testes both in ex vivo and in vivo studies. Its mode of action was found to be through a novel G protein–coupled receptor (GPCR6A) expressed on the surface of Leydig cells. Additional evidence implicating GPCR6A, a 7-transmembrane receptor, as a receptor for osteocalcin was the finding that knockout of this gene in mice results in a phenocopy of the osteocalcin knockout metabolic syndrome.[22] There have been a number of previous studies that investigated the role of estrogen on bone, but the role of osteocalcin regulating testosterone production was novel and somewhat provocative. For example, the addition of osteocalcin to Leydig primary cell cultures provoked an increase in cAMP response element-binding protein through the GPCR6A receptor. This can then act as a transcriptional factor to regulate the synthesis of the key enzymes involved in testosterone production, such as cholesterol side-chain cleavage enzyme (CYP11A1), cytochrome P450 17A (CYP17), and steroidogenic acute regulatory protein (StAR).[23] In vivo proof for the cellular studies used a number of tissue-specific knockouts, as noted in Table 1. Interestingly, a study has shown that Runx2, which controls osteocalcin expression, can also control the expression of CYP11A1 and its shorter isoform that is expressed in osteoblasts. That study showed that up-regulation is through direct binding of Runx2 to the promoter region of CYP11A1.[24] The expression of the Runx family of transcriptional factors, along with CYP11A1 in the testis,[25] is likely more than coincidence and raises some provocative questions about osteocalcin regulation of testosterone, particularly during stages of active bone formation such as pubertal growth.