The role of osteocalcin in regulating the acute stress response

Abstract

Osteocalcin (OCN), a bone-derived hormone, considered as an indicator of bone turnover. Beyond its canonical role in bone metabolism, OCN may have many other functions as well. Studies have shown that it may also regulate glucose and lipid metabolism, cognitive function, sexual function, and more. Recently, OCN has become one interesting hormone with potential effects on acute stress response (ASR), which is essential for vertebrates' survival. This review aims to comprehensively summarize the progress on the role of OCN in the pathophysiology of ASR and to thoroughly analyze the molecular mechanisms and significance of OCN in modulating ASR. In summary, a deeper understanding of OCN's role in the ASR will help reveal how bone-derived signals integrate into stress regulatory networks and may guide the development of novel strategies to prevent or treat stress-related disorders (e.g., anxiety, depression, or stress-aggravated cardiac events). By focusing on the emerging OCN-stress axis, our review highlights an expanding perspective on bone as an endocrine organ influencing stress physiology.

Keywords: HPA axis; acute stress response; anxiety and depression; bone-brain axis; cognition; osteocalcin.

FIGURE 1

OCN during embryonic and postnatal stages affects lifelong adrenal growth, steroidogenesis, and homeostasis (Yadav et al., 2022). OCN derived from embryos is necessary for the normal expression of Sf1 in fetal adrenal cells and the differentiation of adrenal cells into steroid synthesis cells. It determines the number of steroid synthesis cells present in the adult animal adrenal gland and also regulates the development of the adult animal adrenal gland and the synthesis of steroids in the suprarenal gland. After birth, exogenous OCN can enhance steroidogenesis in rodents and non-human primates. OCN, Osteocalcin; Sf1, steroidogenic factor 1.

FIGURE 2

Changes in OCN levels under acute and chronic stress and the effects on the HPA axis. Under acute stress, OCN is secreted in large quantities and promotes the biosynthesis of GC, which inhibits the synthesis and release of OCN. Under chronic stress, OCN levels decrease, leading to impaired negative feedback inhibition of the HPA axis. OCN, Osteocalcin; GC, glucocorticoid.

FIGURE 3

Changes in OCN during ASR and its impact on the autonomic nervous system (Berger and Karsenty, 2022). When exposed to a stressful environment, the stressor sends signals from the basolateral amygdala and other fear centers of the brain, and glutamatergic neurons release the neurotransmitter glutamate, which enters osteoblasts through the transport protein Glast and competitively inhibits GGCX. As a result, levels of uncarboxylated or incompletely carboxylated OCN increase, and uncarboxylated or insufficiently carboxylated OCN can be released into the circulation. They bind to GPRC6A on parasympathetic postganglionic neurons, inhibiting acetylcholine synthesis and reuptake. Therefore, the tension of parasympathetic neurons is inhibited, and the tension of sympathetic neurons is relatively increased, mediating ASR. Gpr158, G protein-coupled receptor 158; GPRC6A, G protein coupled receptor group 6 member a; PNS, parasympathetic nervous system; SNS, sympathetic nervous system; GGCX, gamma-glutamyl carboxylase; ASR, acute stress response.