Roles of osteocalcin in the central nervous system

Abstract

Background: Bone-derived protein osteocalcin, which has beneficial effects on brain function, may be a future research direction for neurological disorders. A growing body of evidence suggests a link between osteocalcin and neurological disorders, but the exact relationship is contradictory and unclear.

Scope of review: The aim of this review is to summarize the current research on the interaction between osteocalcin and the central nervous system and to propose some speculative future research directions.

Major conclusions: In the normal central nervous system, osteocalcin is involved in neuronal structure, neuroprotection, and the regulation of cognition and anxiety. Studies on osteocalcin-related abnormalities in the central nervous system are divided into animal model studies and human studies, depending on the subject. In humans, the link between osteocalcin and brain function is inconsistent. These conflicting data may be due to methodological inconsistencies. By reviewing the related literature on osteocalcin, some comorbidities of the bone and nervous system and future research directions related to osteocalcin are proposed.

Keywords: bone–brain crosstalk; central nervous system; comorbidity; osteocalcin.

FIGURE 1

Osteocalcin synthesis and release. The process by which osteocalcin peptides are carboxylated by vitamin K. Two types of osteocalcin can be generated depending on the amount of vitamin K: Carboxylated osteocalcin, which is involved in osteogenesis, and undercarboxylated osteocalcin, which can enter the blood circulation. The decarboxylation of osteocalcin leads to the production of decarboxylated osteocalcin, which can also enter the circulation and participate in acidic bone resorption by osteoclasts. For simplicity, forms of osteocalcin that enter the brain through the blood–brain barrier or placental barrier and thus function in the blood circulation are collectively known as undercarboxylated osteocalcin (with functions similar to uncarboxylated or decarboxylated osteocalcin). Of course, partially intact carboxylated osteocalcin can also be present in the blood circulation, but this is not shown in the figure.

FIGURE 2

(A) Osteocalcin regulates myelin homeostasis via GPR37. Osteocalcin regulates myelination in oligodendrocytes and affects the thickness of myelin surrounding neurons. OCN, osteocalcin. (B) Effects of maternal osteocalcin on embryos and adult offspring. Maternal osteocalcin can cross the placental barrier, affect neurogenesis in the embryo, and play a neuroprotective role. Maternal osteocalcin affects learning and memory in adult offspring.

FIGURE 3

There are five mechanisms by which osteocalcin regulates cognition and anxiety. After crossing the blood–brain barrier or placental barrier, osteocalcin is known to bind to specific neurons in the brain through five mechanisms. (A) Osteocalcin regulates neurotransmitter release, increasing monoamine neurotransmitter release and reducing GABA release. (B) Osteocalcin increases synaptic plasticity. (C) OCN/GPR158 promotes the synthesis of RbAp48, leading to increased BDNF release. (D) Osteocalcin promotes neurogenesis. (E) Osteocalcin promotes neuronal autophagy. BDNF, brain‐derived neurotrophic factor; GABA, gamma‐aminobutyric acid; MNs, monoamine neurotransmitters.

FIGURE 4

Schematic showing future directions for research on the role of osteocalcin in the central nervous system. (A) Potential mechanisms of osteocalcin in mice with Alzheimer's disease. (B) Potential mechanisms of OCN/GPR37 in neurodegeneration and neuropsychiatric disorders. (C) Osteocalcin is a potential neuropeptide. During anxiety, OCN‐Cre neurons are activated and play an anti‐anxiety role by promoting the expression of brain‐derived neurotrophic factor and adult hippocampal neurogenesis. AD, Alzheimer's disease; AHN, adult hippocampus neurogenesis; BDNF, brain‐derived neurotrophic factor; OCN, osteocalcin.