Osteocalcin and GPR158: linking bone and brain function

Abstract

Osteocalcin (OCN), a small protein secreted by osteoblasts, has attracted significant attention for its role as an endocrine factor in regulating the central nervous system (CNS) via the bone-brain axis. As a critical receptor for OCN, G protein-coupled receptor 158 (GPR158) facilitates the proliferation, differentiation, and survival of neural cells while directly influencing neurons' structural and functional plasticity, thereby modulating cognitive function. Additionally, GPR158 is involved in cellular energy metabolism and interacts with proteins such as regulators of G protein signaling 7 (RGS7), broadening the understanding of OCN's impact on neural activity. Notably, GPR158 displays region- and cell type-specific bidirectional effects under certain pathological conditions, such as tumor development and mood regulation, adding complexity to its mechanisms of action. Although the precise biological mechanisms underlying the OCN/GPR158 signaling pathway remain incompletely understood, its association with neurodegenerative diseases (NDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), is becoming increasingly evident. Thus, a systematic summary of OCN/GPR158 in CNS regulation and NDs will deepen understanding of its role in brain function and support the development of new therapeutic targets and strategies.

Keywords: GPR158; cellular activity; metabolism; neurodegenerative diseases; osteocalcin; synaptic plasticity.

FIGURE 1

Physiological functions of OCN in the bone and brain. OCN, primarily secreted by osteoblasts, plays key roles in bone mineralization, remodeling, and reproduction. Its expression is modulated in part by osteocytes through feedback regulation. Circulating OCN also acts on the brain to influence cognition, mood, and stress responses.

FIGURE 2

GPR158 exhibits different roles in regulating cellular activities in normal and tumor cells. GPR158 facilitates cell proliferation, differentiation, and survival in normal cells by modulating the G1/S checkpoint. Additionally, it suppresses genes associated with the unfolded protein response (UPR). In tumor cells, GPR158 demonstrates dual effects on proliferation, exhibiting context-dependent behavior under high or low activation states.

FIGURE 3

GPR158 influences synaptic plasticity in excitatory neurons through multiple mechanisms. Structurally, the activation of GPR158 enhances the lengths of both the AZ and the PSD. Functionally, GPR158 activation promotes short-term plasticity, such as PPF driven by presynaptic neurotransmitter release, and long-term plasticity, as demonstrated by LTP. The underlying mechanisms may involve GPR158-mediated inhibition of the M-current and increased expression of BDNF. VGCC, Voltage-gated calcium channels; KCNQ, Potassium voltage-gated channel, subfamily Q.

FIGURE 4

The interaction between GPR158 and related proteins. GPR158 interacts with HSPGs and LAR to promote cell differentiation, inhibits β-secretase to reduce Aβ and amyloid plaque formation, and enhances BDNF expression via RbAp48. Additionally, GPR158 binds RGS7, facilitating its membrane localization and forming a negative feedback loop by promoting GTPase activity. GPR158 also interacts with RGS7 to inhibit the GTPase. APP, amyloid precursor protein; C99, β-CTF fragment of APP.