The potential role of bone-derived factor ucOCN in the anti-depressive effects of exercise

Abstract

<p id="p00005">Depression is a major problem in the modern society. The pathogenesis of depression is a research hotspot in the field of neuroscience. The proved mechanisms of depression include monoamine neurotransmitter hypothesis, gene-environment interaction, neurogenesis, neuroplasticity, immune activation and suppression, etc. With the deepening of research, the roles of "brain-gut interaction", "muscle-brain crosstalk", and adipocytokines in the sports antidepressant field has been discovered. As an endocrine organ, the role of bone tissue in anti-depressive exercise remains to be revealed. Based on this, this research innovatively explores the biological effects and mechanisms of uncarboxylated osteocalcin (ucOCN) in exercise anti-depression from the perspective of “bone-brain crosstalk”, and further reveals the relationship between bone endocrine activity and the molecular regulation of sports antidepressant. ucOCN is a specific non-collagen protein secreted by osteoblasts (OB). After entering the blood, it acts on the hippocampus, cingulate gyrus and other brain tissues, and triggers a cascade reaction through targeting cell membrane receptors to regulate neurodevelopment, neuroplasticity and bone endocrine-nerve response system. Exercise promotes the secretion of ucOCN and has a significant antidepressant effect, but there are few studies focusing on the molecular mechanism. Based on integrated biological theory and bone endocrine function, through analysis of current research, we found several mechanisms by which ucOCN mediating exercise antidepressant. Firstly, ucOCN regulates neurotransmitters expression: exercise induces high expression of ucOCN which inhibits γ-amino groups butyric acid (GABA) expression to improve depression-like behavior. Secondly, ucOCN regulates neuroendocrine secretion: ucOCN activates the HPA axis to promote adrenocorticotropic hormone (ACTH), mineralocorticoid, cortisol and other secretions to improve depression-like behavior. In addition, ucOCN also activates G protein-coupled receptors 158 (Gpr158)/brain-derived neurotrophic factor (BDNF) pathway to promote neurotransmitter secretion and further regulate depression occurring. Thirdly, ucOCN regulates neuroimmunity: ucOCN activates the ERK and STAT pathways and down-regulates the expression of IL-6 and IL-8 in the hippocampus, and then through malondialdehyde (MDA)/super up-regulation of superoxide dismutase (SOD)/nuclear factor erythroid-derived 2-like 2(Nrf2)/heme oxygenase 1(HO1) pathway to increase expression of VGF and BDNF, which further improve depression-like behaviors. Taken together, these results provide a solid theoretical basis for the mechanism of ucOCN in sports anti-depression. We also provides new research directions and ideas for sports anti-depression, and provide a new perspective for enriching the biological mechanism network of sports brain.