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.

This study by Khrimian et al. demonstrates that the bone-derived hormone osteocalcin is necessary and sufficient to correct age-related cognitive decline in the mouse. It also provides genetic, molecular, and neurophysiological evidence that Gpr158 is the receptor mediating osteocalcin’s regulation of cognition.

Highlights d The ASR stimulates osteocalcin release from bone within minutes d Glutamate uptake into osteoblasts is required for osteocalcin release during an ASR d Osteocalcin inhibits the parasympathetic tone during an ASR d In adrenal insufficiency, increased osteocalcin levels enable an ASR to occur

A remarkable, totally unexpected aspect of the bone-derived hormone osteocalcin is that it is necessary for both brain development and brain function in the mouse since its absence results in a profound deficit in spatial learning and memory and an exacerbation of anxiety-like behavior. The regulation of cognitive function by osteocalcin, together with the fact its circulating levels decrease in midlife compared to adolescence in all species tested raised the prospect that osteocalcin may be an anti-geronic hormone that could prevent age-related cognitive decline. As presented in this review, recent data indicate that this is indeed the case and that osteocalcin is necessary for the anti-geronic activity recently ascribed to the plasma of young WT mice. The diversity and amplitude of the functions of osteocalcin in the brain during development and postnatally had long called for the identification of its receptor in the brain, which was also recently achieved. This review presents our current understanding of osteocalcin's biology in the brain, highlighting the bony-vertebrate specificity of the regulation of cognitive function, and pointing toward where therapeutic opportunities may exist.

ObjectiveThat the bone-derived hormone osteocalcin is necessary to promote normal brain development and function, along with its recently described sufficiency in reversing cognitive manifestations of aging, raises novel questions. One of these is to assess whether bone health, which deteriorates rapidly with aging, is a significant determinant of cognition and anxiety-like behavior.MethodsTo begin addressing this question, we used mice haploinsufficient for Runx2, the master gene of osteoblast differentiation and the main regulator of Osteocalcin expression. Control and Runx2+/− mice were evaluated for the expression of osteocalcin's target genes in the brain and for behavioral parameters, using two assays each for cognition and anxiety-like behavior.ResultsWe found that adult Runx2+/− mice had defects in bone resorption, reduced circulating levels of bioactive osteocalcin, and reduced expression of osteocalcin's target genes in the brain. Consequently, they had significant impairment in cognitive function and increased anxiety-like behavior.ConclusionsThese results indicate that bone remodeling is a determinant of brain function.