Osteocalcin in the brain: from embryonic development to age-related decline in cognition

Obri, Arnaud; Khrimian, Lori; Karsenty, G.; Oury, Franck

doi:10.1038/nrendo.2017.181

Cited by 153 publications

(107 citation statements)

References 87 publications

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“…RUNX2 gene encodes a transcription factor that regulates the expression of osteocalcin (16). Interestingly, low osteocalcin level is associated with age-related decline in cognitive function, which may contribute to the association between this RUNX2 variant and RBA (17,18). NKX6-2 encodes a transcription factor that regulates myelin sheath formation and maintenance in the central nervous system (19,20).…”

Section: Discussionmentioning

confidence: 99%

Improving brain age estimates with deep learning leads to identification of novel genetic factors associated with brain aging

Ning

Duffy

Franklin

et al. 2020

Preprint

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Brain aging trajectories among those of the same chronological age can vary significantly. Statistical models have been created for estimating the apparent age of the brain, or predicted brain age, with imaging data. Recently, convolutional neural networks (CNNs) have shown the potential to more accurately predict brain age. We trained a CNN on 16,998 UK Biobank subjects, and in validation tests found that it was more accurate than a regression model for predicting brain age. A genome-wide association study was conducted on CNN-derived predicted brain age whereby we identified single nucleotide polymorphisms from four independent loci significantly associated with brain aging. One locus has been previously reported to be associated with brain aging. The three other loci were novel. Our results suggest that a more accurate brain age prediction enables the discovery of novel genetic associations, which may be valuable for identifying other lifestyle factors associated with brain aging.

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Section: Discussionmentioning

confidence: 99%

Improving brain age estimates with deep learning leads to identification of novel genetic factors associated with brain aging

Ning

Duffy

Franklin

et al. 2020

Preprint

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“…Other observed endocrine roles for OCN include influencing fetal brain development and adult animal behavior [8], and promoting adaptation of myofibers to exercise and maintaining muscle mass with ageing [9,10]. Cumulatively, the reports outlined above with the Osc -/Oscmice and, subsequently, a conditional knockout strain (Ocn-flox) made by the same investigative team [7] coupled with associated work [11][12][13][14][15][16][17][18] from this team, suggest that therapies which increase uncarboxylated osteocalcin levels may improve glucose intolerance, increase beta islet cell number, reduce insulin resistance, increase testosterone, improve male fertility, enhance muscle mass, and reduce declines in cognition.…”

Section: Introductionmentioning

confidence: 99%

An Osteocalcin-deficient mouse strain without endocrine abnormalities

Diegel

Hann

Ayturk

et al. 2019

Preprint

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Osteocalcin (OCN), the most abundant non-collagenous protein in the bone matrix, is reported to be a bone-derived endocrine hormone with wide-ranging effects on many aspects of physiology, including glucose metabolism and male fertility. Many of these observations were made using an OCN-deficient mouse allele (Osc -) in which the 2 OCN-encoding genes in mice, Bglap and Bglap2, were deleted in ES cells by homologous recombination. Here we describe mice with a new Bglap and Bglap2 double knockout (dko) allele (Bglap/2 p.Pro25fs17Ter ) that was generated by CRISPR/Cas9-mediated gene editing. Mice homozygous for this new allele do not express full length Bglap or Bglap2 mRNA and have no immunodetectable OCN in their plasma. FTIR imaging of cortical and trabecular bone in these homozygous knockout animals finds alterations in the crystal size and maturity of the bone mineral, hydroxyapatite, compared to wild-type littermates; however, µCT and 3-point bending tests do not find differences from wild-type littermates with respect to bone mass and strength. In contrast to the previously reported OCN-deficient mice with the Oscallele, blood glucose levels and male fertility in the OCN-deficient mice with Bglap/2 pPro25fs17Ter allele did not have significant differences from wild-type littermates. We cannot explain the absence of endocrine effects in mice with this new knockout allele. Potential explanations include effects of each mutated allele on the transcription of neighboring genes, and differences in genetic background and environment. So that our findings can be confirmed and extended by other interested investigators, we are donating this new Bglap and Bglap2 double knockout strain to The Jackson Laboratory for academic distribution. Author SummaryCells that make and maintain bone express proteins that function locally or systemically. The former proteins, such as type 1 collagen, affect the material properties of the skeleton while the latter proteins, such as fibroblast growth factor 23, enable the skeleton to communicate with other organ systems. Mutations that affect the functions of most bone cell expressed proteins cause diseases that have similar features in humans and other mammals, such as mice; for example, brittle bone diseases for type 1 collagen mutations and hypophosphatemic rickets for fibroblast growth factor 23 mutations.Our study focuses on another bone cell expressed protein, osteocalcin, which has been suggested to function locally to affect bone strength and systemically as hormone. Studies using osteocalcin knockout mice led other investigators to suggest endocrine roles for osteocalcin in regulating blood glucose levels, male fertility, muscle mass, brain development, behavior and cognition. We therefore decided to generate a new strain of osteocalcin knockout mice that could also be used to investigate these non-skeletal effects.To our surprise the osteocalcin knockout mice we created do not significantly differ from wildtype mice for the 3 phenotypes we examined: bone strength, blood glucos...

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“…Increasing clinical evidence indicated that patients with PD have a higher susceptibility to another very common age-related disease–osteoporosis (Torsney et al, 2014 ). The cross-talk between bone and brain was suggested by a series of works from Karsenty’s group revealing that bone-derived osteocalcin (OCN) is important for brain development (Obri et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Osteocalcin Ameliorates Motor Dysfunction in a 6-Hydroxydopamine-Induced Parkinson’s Disease Rat Model Through AKT/GSK3β Signaling

Guo

Shan

Hou

et al. 2018

Front. Mol. Neurosci.

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Osteoblasts derived osteocalcin (OCN) is recently reported to be involved in dopaminergic neuronal development. As dopaminergic neuronal injury in the substantia nigra (SN) is a pathological hallmark of Parkinson’s disease (PD), we investigated whether OCN could exert protective effects on 6-hydroxydopamine (6-OHDA)-induced PD rat model. Our data showed that the OCN level in the cerebrospinal fluid (CSF) in PD rat models was significantly lower than that in controls. Intervention with OCN could improve the behavioral dysfunction in PD rat models and reduce the tyrosine hydroxylase (TH) loss in the nigrostriatal system. In addition, OCN could inhibit the astrocyte and microglia proliferation in the SN of PD rats. In vitro studies showed that OCN significantly ameliorated the neurotoxicity of 6-OHDA through the AKT/GSK3β signaling pathway. In summary, OCN plays a protective role against parkinsonian neurodegeneration in the PD rat model, suggesting a potential therapeutic use of OCN in PD.

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Osteocalcin in the brain: from embryonic development to age-related decline in cognition

Cited by 153 publications

References 87 publications

Improving brain age estimates with deep learning leads to identification of novel genetic factors associated with brain aging

Improving brain age estimates with deep learning leads to identification of novel genetic factors associated with brain aging

An Osteocalcin-deficient mouse strain without endocrine abnormalities

Osteocalcin Ameliorates Motor Dysfunction in a 6-Hydroxydopamine-Induced Parkinson’s Disease Rat Model Through AKT/GSK3β Signaling

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