Embryonic osteocalcin signaling determines lifelong adrenal steroidogenesis and homeostasis in the mouse

Abstract

Through their ability to regulate gene expression in most organs, glucocorticoid hormones influence numerous physiological processes and therefore are key regulators of organismal homeostasis. In bone, glucocorticoid hormones inhibit the expression of the hormone Osteocalcin for poorly understood reasons. Here we show that in a classical endocrine feedback loop, osteocalcin in return enhances the biosynthesis of glucocorticoid but also mineralocorticoid hormones (adrenal steroidogenesis) in rodents and primates. Conversely, inactivating osteocalcin signalling in adrenal glands significantly impairs adrenal growth and steroidogenesis in mice. Embryo-made osteocalcin is necessary for normal Sf1 expression in foetal adrenal cells and adrenal cell steroidogenic differentiation, it therefore determines the number of steroidogenic cells present in adrenal glands of adult animals. Embryonic not postnatal osteocalcin also governs adrenal growth, adrenal steroidogenesis, blood pressure, electrolyte equilibrium and the rise of circulating corticosterone during the acute stress response in adult offspring. This osteocalcin-dependent regulation of adrenal development and steroidogenesis occurs even in the absence of a functional of hypothalamus-pituitary-adrenal axis; this explains why osteocalcin administration during pregnancy promotes adrenal growth and steroidogenesis and improves survival of adrenocorticotropic hormone signalling-deficient animals. This study reveals that a bonederived, embryonic hormone influences lifelong adrenal functions and organismal homeostasis in the mouse.

Osteocalcin and the physiology of danger

“…Remarkably, either one of these two manipulations was also sufficient to increase the circulating levels of aldosterone the mineralocorticoid hormone synthesised by cells of the glomerulosa layer in the cortex of adrenal glands. These results suggested that osteocalcin might be a regulator of adrenal steroidogenesis, that is, glucocorticoid and mineralocorticoid hormones biosynthesis [ 159 ]. Given the complexity of the regulation of adrenal steroidogenesis that involves numerous molecules and multiple organs addressing this question required first to determine where is the receptor of osteocalcin expressed along the hypothalamo–pituitary–adrenal (HPA) axis or the renin–angiotensin system (RAS)?…”

“…What this analysis showed is that one of the three receptors of osteocalcin, Gpr158, is expressed in the adrenal cortex and in no other relevant tissues, and that mice lacking Gpr158 in all cells or in cells of adrenal cortex develop an adrenal insufficiency characterised by low circulating corticosterone and aldosterone, high blood potassium concentration, and lower blood pressure. Hence, osteocalcin signalling in the adrenal glands is not only sufficient to promote adrenal steroidogenesis, it is also necessary for this process, even in the presence of a functional HPA axis and RAS [ 159 ].…”

“…As a result of this function, in the absence of embryonic osteocalcin differentiation of cells of the adrenal cortex is hampered and the number of these cells in the adrenal cortex is significantly decreased during embryonic development and throughout life. Remarkably, the absence of osteocalcin only after birth does not affect adrenal steroidogenesis, indicating that this is a specific function or set of functions of embryonic osteocalcin [ 159 ]. This most recent work not only adds credence to the notion that osteocalcin may contribute to the response of bony vertebrates to an acute danger, suggests that many cross-talks between organs remain to be discovered, but it also reveals that embryonic osteocalcin, which for a long time was not considered as biologically important, has its own set of functions.…”

The emerging roles of GPR158 in the regulation of the endocrine system

“…In nerve growth factor-induced neurite outgrowth of PC12 cells, OCN interacts with GPR158 and promotes PC12 cell proliferation, differentiation, and survival (Ando et al, 2021). Embryonic OCN/ GPR158 signals determine lifelong adrenal steroidogenesis and homeostasis in the adrenal gland of mice (Yadav et al, 2022). Indeed, steroid hormones, such as glucocorticoids and androgens, can interact with GPR158.…”

“…In estrogen-sensitive breast cancer, the expression of GPR158 is down-regulated following the withdrawal of estrogen or the use of estrogen antagonists (Salazar et al, 2011), suggesting that GPR158 may be a novel biomarker for the prognosis of ovarian carcinoma and breast cancer. Recently, a study on OCN regulation of adrenal steroidogenesis in mice revealed that GPR158 is expressed in the adrenal gland, and the expression level is significantly higher than in the hypothalamus and pituitary gland (Yadav et al, 2022). Overall, despite the expression level of GPR158 in peripheral endocrine tissues being lower than that in nervous tissue, this does not influence its physiological role owing to the powerful effects of hormones.…”