Abstract
Through their ability to regulate gene expression in most organs, glucocorticoid (GC) hormones influence numerous physiological processes and are therefore key regulators of organismal homeostasis. In bone, GC hormones inhibit expression of the hormone Osteocalcin for poorly understood reasons. Here, we show that in a classical endocrine feedback loop, osteocalcin in return enhanced the biosynthesis of GC as well as mineralocorticoid hormones (adrenal steroidogenesis) in rodents and primates. Conversely, inactivation of osteocalcin signaling in adrenal glands significantly impaired adrenal growth and steroidogenesis in mice. Embryo-made osteocalcin was necessary for normal Sf1 expression in fetal adrenal cells and adrenal cell steroidogenic differentiation and therefore determined the number of steroidogenic cells present in the adrenal glands of adult animals. Embryonic, not postnatal, osteocalcin also governed adrenal growth, adrenal steroidogenesis, blood pressure, electrolyte equilibrium, and the rise in circulating corticosterone levels during the acute stress response in adult offspring. This osteocalcin-dependent regulation of adrenal development and steroidogenesis occurred even in the absence of a functional hypothalamus/pituitary/adrenal axis and explains why osteocalcin administration during pregnancy promoted adrenal growth and steroidogenesis and improved the survival of adrenocorticotropic hormone signaling–deficient animals. This study reveals that a bone-derived embryonic hormone influences lifelong adrenal functions and organismal homeostasis in the mouse.
Highlights
The adrenal gland, an organ of fundamental importance in mammals, is composed of two distinct areas
We observed that Esposb-/- mice that lacked one allele of Osteocalcin had normal circulating osteocalcin, corticosterone and aldosterone levels indicating that osteocalcin favors adrenal steroidogenesis as a bone-derived molecule (Figure 1G, J-K)
Based on the higher expression of their receptors, these observations suggest that osteocalcin may increase adrenocorticotropic hormone (ACTH) and angiotensin 2 signaling in adrenal glands
Summary
The adrenal gland, an organ of fundamental importance in mammals, is composed of two distinct areas. Adrenal development is initiated and largely controlled by the transcription factor steroidogenic factor 1 (SF1) [1, 5]. Sf1-expressing fetal adrenal cells give rise to, Gli1-positive, Sf1-negative non-steroidogenic adrenocortical progenitor cells located in the capsule surrounding the developing gland [1, 5]. These adrenocortical progenitor cells differentiate into Sf1-positive aldosterone-producing cells that move centripetally. GCproducing cells originate largely from aldosterone-producing ones through lineage conversion, a process that is dependent on Sf1 [1, 5]
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