Maternal and Offspring Pools of Osteocalcin Influence Brain Development and Functions

Abstract

The powerful regulation of bone mass exerted by the brain suggests the existence of bone-derived signals modulating this regulation or other functions of the brain. We show here that the osteoblast-derived hormone osteocalcin crosses the blood-brain barrier, binds to neurons of the brainstem, midbrain and hippocampus, enhances the synthesis of monoamine neurotransmitters, inhibits GABA synthesis, prevents anxiety and depression and favors learning and memory independently of its metabolic functions. In addition to these post-natal functions, maternal osteocalcin crosses the placenta during pregnancy and prevents neuronal apoptosis before embryos synthesize this hormone. As a result the severity of the neuro-anatomical defects and learning and memory deficits of Osteocalcin−/− mice is determined by the maternal genotype, and delivering osteocalcin to pregnant Osteocalcin−/− mothers rescues these abnormalities in their Osteocalcin−/− progeny. This study reveals that the skeleton via osteocalcin influences cognition and contributes to the maternal influence on fetal brain development.

Bone-brain crosstalk and potential associated diseases

“…Clinical studies have correlated features of bone metabolism in women with MDD indicating that depressed women had lower bone mass and lower levels of Ocn compared to healthy subjects [120,121]. Moreover, it is known that the antidepressant drugs SSRIs decrease bone mass and increase the risk of fractures, which is consistent with the role of brain-derived serotonin on bone physiology [118,[122][123][124][125].…”

The “soft” side of the bone: unveiling its endocrine functions

“…What is most surprising though, is that bone can also influence cognitive functions, again through Ocn [107]. The study showing this regulation started because the Ocn −/− mice showed unusual passiveness and unwillingness to deambulate, as they quantified using the open field test [107]. Intriguingly, no difference was detected in OcnR −/− mice, suggesting that the mechanism is not mediated by this G-protein coupled receptor.…”

“…Many brain-derived signals have been shown to regulate bone accrual and remodeling, especially through the sympathetic nervous system that is able to regulate both osteoblasts and osteoclasts at the same time [89,108,109]. What is most surprising though, is that bone can also influence cognitive functions, again through Ocn [107]. The study showing this regulation started because the Ocn −/− mice showed unusual passiveness and unwillingness to deambulate, as they quantified using the open field test [107].…”

“…We have been through a series of unexpected regulatory mechanisms mediated by an osteoblast-derived hormone, Ocn, but perhaps the most interesting effect it mediates is about brain development and efficiency [107]. Many brain-derived signals have been shown to regulate bone accrual and remodeling, especially through the sympathetic nervous system that is able to regulate both osteoblasts and osteoclasts at the same time [89,108,109].…”

Does Defective Bone Lead to Defective Muscle?

“…This raises the question of whether bone factors such as osteocalcin only regulate specific muscle fibers or if other factors exist to regulate myogenesis, fast or slow muscle fibers, or a combination. Does this new data mean that regulation of muscle fiber type can now be added to the many other functions of murine osteocalcin, including glucose metabolism, energy metabolism, (21) fetal brain development, (22) fertility, (23) and ectopic calcification? (24) The role of mechanical loading in this Cx43 deletion model is not clear.…”