ESPE Yearbook of Paediatric Endocrinology

J Clin Invest 2022;132(4):e153752 doi: 10.1172/JCI153752

Brief summary: Using rodent and primate models, this study shows a classical endocrine feedback loop, where bone-derived osteocalcin enhances adrenal steroidogenesis, and the inactivation of osteocalcin signalling impairs adrenal growth and steroidogenesis.

This study provides important evidence on the existence of the bone/adrenal axis and its effect on fetal adrenal development and reveals that bone-derived osteocalcin (Ocn) modulates fetal adrenal homeostasis, termed the ‘bone-adrenal endocrine circuit’ [additional commentary is provided by Dumontet & Hammer 2022]. The authors showed that Ocn injections increased circulatory corticosterone (to a similar extent as observed with adrenocorticotropic hormone) and aldosterone (also observed in rhesus monkeys), together with the upregulation of melanocortin receptor 2 (Mc2r) and steroid 11β-monooxygenases, Cyp11b1 and Cyp11b2, expression. Moreover, Ocn-deficient (Ocn^–/–) mice born from Ocn^–/– parents showed lower corticosterone and aldosterone levels and decreased expression of Cyp11b1 and Cyp11b2 compared to WT mice and Ocn^–/– mice born from a cross between Ocn^+/– parents. Ocn signalling during fetal development assisted murine adrenal gland growth, and the authors concluded that embryologic Ocn may regulate adrenal steroidogenesis and adult adrenal function.

The initiation of this study worked in reverse, starting from the question: if glucocorticoids (GC) influence Ocn expression, then perhaps Ocn influences GC production. Rewardingly, inferring that Ocn regulates GC biosynthesis established an important link between bone formation and adrenal development, and underscores Ocn signalling as an important factor in the lifelong regulation of adrenal growth and steroidogenesis. As exciting as this research is, further studies now have to prove the relevance of the bone/adrenal axis to human fetal adrenal development and human biology, while the translational potential of targeting Ocn to modulate adrenal function also remains to be elucidated.

Reference: 1. Dumontet T, Hammer GD. Bones and adrenal organogenesis: how embryonic osteocalcin influences lifelong adrenal function. J Clin Invest 2022;132(4):e157200, doi: 10.1172/JCI157200.