Embryonic osteocalcin signaling determines lifelong adrenal steroidogenesis and homeostasis in the mouse
Vijay K. Yadav, … , Perumal Nagarajan, Gerard Karsenty
Vijay K. Yadav, … , Perumal Nagarajan, Gerard Karsenty
Published December 14, 2021
Citation Information: J Clin Invest. 2022;132(4):e153752. https://doi.org/10.1172/JCI153752.
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Research Article Bone biology Metabolism

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

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.

Authors

Vijay K. Yadav, Julian M. Berger, Parminder Singh, Perumal Nagarajan, Gerard Karsenty

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Figure 8

Osteocalcin induces adrenal steroidogenesis and growth in the absence of ACTH signaling.

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Osteocalcin induces adrenal steroidogenesis and growth in the absence of...
(A) Circulating corticosterone levels following an acute ACTH challenge at 1000 hours in adult WT and Gpr158sf1–/– mice born from a Gpr158fl/fl female mouse crossed with a Gpr158fl/fl Sf1-Cre+ male mouse. (B) Gpr158 expression in adrenal glands of WT and Mc2r–/– newborn mice. (C) Adrenal Gpr158 expression in WT mice 2 hours after ACTH challenge. (D) Intra-adrenal content of corticosterone and aldosterone in P1 WT, Mc2r+/–, Gpr158Sf1+/–, and Mc2r+/– Gpr158Sf1+/– mice born from Mc2r+/– Gpr158Sf1+/– parents. (E and F) Adrenal Mc2r (E), Gpr158 (E), Cyp11b1, and Cyp11b2 (F) expression in WT and Mc2r+/– newborn mice. (G and H) H&E-stained sections of adrenal glands (G) and ISH analysis of adrenal Gli1, Cyp11b2, and Cyp11b1 expression (H) in E18.5 WT and Mc2r–/– embryos collected from Mc2r+/– mothers that received either vehicle or osteocalcin (300 ng/day) from E10.5 to E18.5. Scale bars: 250 μm (G) and 100 μm (H). (I and J) Intra-adrenal content of corticosterone (I) and aldosterone (J) in WT and Mc2r–/– newborn mice born from Mc2r+/– mothers that received vehicle or osteocalcin (300 ng/day) from E10.5 until birth. Statistical analyses were conducted using 1-way ANOVA followed by Tukey’s post hoc test (A, D, I, and J) or 2-tailed, unpaired t test (B, C, E, and F). *P < 0.05. n = 6 or more embryos or offspring in each group.