Roles for osteocalcin in brain signalling: implications in cognition- and motor-related disorders

Abstract

It is now generally accepted that the extra-skeleton functionalities of bone are multifaceted. Its endocrine functions came first to light when it was realized that osteoblasts, the bone forming cells, maintain energy homeostasis by improving glucose metabolism, insulin sensitivity and energy expenditure through osteocalcin, a multipurpose osteokine secreted by osteoblasts. Recently, the emerging knowledge on the functional aspects of this osteokine expanded to properties including adult and maternal regulation of cognitive functions. Therapeutic potential of this osteokine has also been recently reported in experimental Parkinson's disease models. This review highlights such findings on the functions of osteocalcin in the brain and emphasizes on exploring and analyzing much more in-depth basic and clinical studies.

Keywords: Behavior; Bone; Brain; Cognition; Osteocalcin; Parkinson’s disease.

Fig. 1

The neuroprotective effects of osteocalcin (OCN) in rats with Parkinson’s disease (PD). OCN, administered either peripherally or centrally, ameliorates motor dysfunction, reduces dopaminergic neuronal loss and diminishes glia-mediated inflammatory responses in PD rat model induced by 6-OHDA via the AKT/GSK3β signaling pathway

Fig. 2

The possible therapeutic implications of resveratrol/metformin/exercise in cognition through osteocalcin signalling. Resveratrol, metformin and exercise have all been reported to have benefical effects on cognition improvements, which might have a link with their regulation on osteocalcin (OCN) from our point of view. Briefly, resveratrol on one hand can induce the expression of OCN, which has been found to improve age-related cognitive decline via the GRP158/Gad/IP3 pathway, in human bone marrow mesenchymal stem cells, murine MC3T3 and ST2 cell lines by decreasing nuclear translocation of the NF-κB; on the other hand, several common pathways of SIRT1 activated by resveratrol on the regulation of OCN and cognition, such as improved insulin sensititvity, improved glucose metabolism, reduced oxidative stress and inflammation through the suppression of NF-κB, give rise to the possible link between resveratrol/SIRT1 and OCN. Metformin could attenuate bone loss and increase bone regeneration capability through increased expression of OCN, via a mechanism related to AMPK, and regulate behaviours through upregulation of BDNF, which is related to the beneficial actions of OCN in age-related memory loss. These findings suggest a putative link between metformin therapy and brain functions wherein OCN may act as a facilitator of the improved cognitive functions by metformin through improvement of neurotrophic signaling and energy metabolism, and through modulation of inflammatory reactions. An exercise-induced activation of the IL-6/OCN/gp130 axis that in turn improves energy homeostasis and thereby improves cognition could be another plausible explanation of why interventional strategies such as exercise can improve cognitive ability.