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The Journal of Experimental Medicine Oct 2017That osteocalcin (OCN) is necessary for hippocampal-dependent memory and to prevent anxiety-like behaviors raises novel questions. One question is to determine whether...
That osteocalcin (OCN) is necessary for hippocampal-dependent memory and to prevent anxiety-like behaviors raises novel questions. One question is to determine whether OCN is also sufficient to improve these behaviors in wild-type mice, when circulating levels of OCN decline as they do with age. Here we show that the presence of OCN is necessary for the beneficial influence of plasma from young mice when injected into older mice on memory and that peripheral delivery of OCN is sufficient to improve memory and decrease anxiety-like behaviors in 16-mo-old mice. A second question is to identify a receptor transducing OCN signal in neurons. Genetic, electrophysiological, molecular, and behavioral assays identify , an orphan G protein-coupled receptor expressed in neurons of the CA3 region of the hippocampus, as transducing OCN's regulation of hippocampal-dependent memory in part through inositol 1,4,5-trisphosphate and brain-derived neurotrophic factor. These results indicate that exogenous OCN can improve hippocampal-dependent memory in mice and identify molecular tools to harness this pathway for therapeutic purposes.
Topics: Aging; Animals; CA3 Region, Hippocampal; Cognition; Electrophysiology; Female; Male; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteocalcin; Receptors, G-Protein-Coupled
PubMed: 28851741
DOI: 10.1084/jem.20171320 -
American Journal of Human Biology : the... Sep 2020Investigating factors that contribute to bone loss and accretion across populations in remote settings is challenging, particularly where diagnostic tools are scarce. To...
OBJECTIVES
Investigating factors that contribute to bone loss and accretion across populations in remote settings is challenging, particularly where diagnostic tools are scarce. To mitigate this challenge, we describe validation of a commercial ELISA assay to measure osteocalcin, a biomarker of bone formation, from dried blood spots (DBS).
METHODS
We validated the Osteocalcin Human SimpleStep ELISA kit from Abcam (ab1951214) using 158 matched plasma and DBS samples. Passing-Bablok regression analysis assessed the relationships between plasma and DBS osteocalcin concentrations. Dilutional linearity and spike and recovery experiments determined if the DBS matrix interfered with osteocalcin measurement, and intra- and inter-assay coefficients of variation (CVs) were calculated. Limit of detection, analyte stability, and specific forms of osteocalcin measured by the kit were also investigated.
RESULTS
Mean plasma osteocalcin value was 218.2 ng/mL (range 64.6-618.1 ng/mL). Linear relationships existed between plasma and DBS concentrations of osteocalcin, with no apparent bias in plasma vs DBS concentrations. There was no apparent interference of the DBS matrix with measurement of osteocalcin in DBS. Intra-assay CV for DBS was ~8%, while average inter-assay CV was 14.8%. Limit of detection was 0.34 ng/mL. Osteocalcin concentrations were stable in DBS stored at -28°C and room temperature, but not those stored at 37°C. This ELISA kit detects total osteocalcin.
CONCLUSIONS
Osteocalcin, a bone formation biomarker, can be measured from DBS. Combined with a previously validated DBS assay for TRACP-5b, a bone resorption biomarker, these assays have the potential to help researchers disentangle the many factors contributing to bone strength.
Topics: Adult; Aged; Biomarkers; Dried Blood Spot Testing; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Oregon; Osteocalcin; Osteogenesis; Reproducibility of Results; Young Adult
PubMed: 32017301
DOI: 10.1002/ajhb.23394 -
Oncotarget Aug 2015
Topics: 1-Carboxyglutamic Acid; Animals; Humans; Mice; Osteocalcin
PubMed: 26343369
DOI: 10.18632/oncotarget.5126 -
Critical Reviews in Clinical Laboratory... 1991Osteocalcin is a small (Mr 5800), very interesting bone specific protein, synthesized by osteoblasts and measured in plasma as a biochemical indicator of bone formation.... (Review)
Review
Osteocalcin is a small (Mr 5800), very interesting bone specific protein, synthesized by osteoblasts and measured in plasma as a biochemical indicator of bone formation. Many immunoassays for osteocalcin have been developed, including radio- and enzymoimmunoassays, with the use of monoclonal and polyclonal antibodies. These are used in many different clinical settings, including bone, kidney, and liver diseases. However, there is a wide range of published values for plasma osteocalcin concentrations in control and patient samples and this has hindered a more widespread adoption of osteocalcin measurement by clinicians. This review discusses how various immunoassays for osteocalcin may contribute to the wide variation of published values and suggests approaches for the development of standardized assays. For example, epitope specificity and immunoreactivity with multiple forms of osteocalcin and osteocalcin peptides in plasma are discussed. It also includes a recent update on interesting clinical applications of osteocalcin.
Topics: Aging; Amino Acid Sequence; Bone Neoplasms; Bone Remodeling; Female; Humans; Hyperthyroidism; Immunoassay; Male; Molecular Sequence Data; Osteocalcin; Osteoporosis; Sex Factors
PubMed: 1930680
DOI: 10.3109/10408369109106867 -
Journal of Cellular Biochemistry Mar 1995Osteocalcin is a skeletal member of the family of extracellular mineral binding Gla protein. Osteocalcin is synthesized only by the osteoblast and it is secreted into... (Review)
Review
Osteocalcin is a skeletal member of the family of extracellular mineral binding Gla protein. Osteocalcin is synthesized only by the osteoblast and it is secreted into the bone matrix at the time of bone mineralization. The mineral binding properties of osteocalcin as well as its spatial and temporal pattern of expression suggest that it plays a role during bone mineralization, however until now its biological function is unclear. To understand osteocalcin function during skeletogenesis we mutated the two osteocalcin genes by homologous recombination in embryonic stem (ES) cells. Eight targeted clones were identified by Southern analysis using external probes. One of these clones contributed to the germ line of mouse chimera. Interbreeding of heterozygotes is currently in progress. Mutant mice will be useful to understand osteocalcin function in vivo.
Topics: Animals; Gene Expression Regulation, Developmental; Mice; Multigene Family; Osteocalcin
PubMed: 7768973
DOI: 10.1002/jcb.240570302 -
EMBO Reports Feb 2024Many physiological osteocalcin-regulated functions are affected in adult offspring of mothers experiencing unhealthy pregnancy. Furthermore, osteocalcin signaling during...
Many physiological osteocalcin-regulated functions are affected in adult offspring of mothers experiencing unhealthy pregnancy. Furthermore, osteocalcin signaling during gestation influences cognition and adrenal steroidogenesis in adult mice. Together these observations suggest that osteocalcin may broadly function during pregnancy to determine organismal homeostasis in adult mammals. To test this hypothesis, we analyzed in unchallenged wildtype and Osteocalcin-deficient, newborn and adult mice of various genotypes and origin maintained on different genetic backgrounds, the functions of osteocalcin in the pancreas, liver and testes and their molecular underpinnings. This analysis revealed that providing mothers are Osteocalcin-deficient, Osteocalcin haploinsufficiency in embryos hampers insulin secretion, liver gluconeogenesis, glucose homeostasis, testes steroidogenesis in adult offspring; inhibits cell proliferation in developing pancreatic islets and testes; and disrupts distinct programs of gene expression in these organs and in the brain. This study indicates that osteocalcin exerts dominant functions in most organs it influences. Furthermore, through their synergistic regulation of multiple physiological functions, osteocalcin of maternal and embryonic origins contributes to the establishment and maintenance of organismal homeostasis in newborn and adult offspring.
Topics: Animals; Female; Humans; Mice; Pregnancy; Blood Glucose; Homeostasis; Insulin; Insulin Secretion; Mammals; Osteocalcin; Prenatal Exposure Delayed Effects
PubMed: 38228788
DOI: 10.1038/s44319-023-00031-3 -
Endocrine Oct 2017Osteocalcin is considered as a bone-derived hormone affecting on the body fat distribution and body mass index. Several cross-sectional studies have investigated the... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Osteocalcin is considered as a bone-derived hormone affecting on the body fat distribution and body mass index. Several cross-sectional studies have investigated the association between serum osteocalcin and body mass index. The aim of this study was to summarize the evidence on the relationship between serum osteocalcin and body mass index.
METHODS
We conducted a complete search up to November 2016 in PubMed and SCOPUS and reviewed reference list of all relevant articles and reviews. The DerSimonian-Laird method were used to pool effect sizes of eligible studies. The potential sources of heterogeneity were assessed using the standard χ test.To find possible the sources of between-study heterogeneity, we carried out subgroup analyses based on sex, and type of study population.
RESULTS
There was a significant inverse association in the overall result of this study between serum osteocalcin levels and BMI(r = -0.161; 95% CI: -0.197, -0.124, p < 0.000). In the subgroup analysis to find the sources of significant heterogeneity between-study, we observed that the type of the study population may be the source of between-study heterogeneity and the most correlation was seen in metabolic syndrome studies (r = -0.265; p = 0.000).
CONCLUSION
Findings from the available data indicated an overall significant inverse association between serum osteocalcin and body mass index. Further studies based on the type of study population are needed to better clarify these associations.
Topics: Animals; Body Mass Index; Humans; Metabolic Syndrome; Obesity; Osteocalcin
PubMed: 28822067
DOI: 10.1007/s12020-017-1384-4 -
Biochimica Et Biophysica Acta. General... Mar 2021The carboxylation status of Osteocalcin (Ocn) not only influences formation and structure in bones but also has important endocrine functions affecting energy metabolism... (Review)
Review
BACKGROUND
The carboxylation status of Osteocalcin (Ocn) not only influences formation and structure in bones but also has important endocrine functions affecting energy metabolism and expenditure. In this study, the role of γ-carboxylation of the glutamate residues in the structure-dynamics-function relationship in Ocn is investigated.
METHODS
Three forms of Ocn, differentially carboxylated at the Glu-17, 21 and 24 residues, along with a mutated form of Ocn carrying Glu/Ala mutations, are modeled and simulated using molecular dynamics (MD) simulation in the presence of calcium ions.
RESULTS
Characterization of the global conformational dynamics of Ocn, described in terms of the orientational variations within its 3-helical domain, highlights large structural variations in the non-carboxylated osteocalcin (nOcn). The bi-carboxylated Ocn (bOcn) and tri-carboxylated (tOcn) species, in contrast, display relatively rigid tertiary structures, with the dynamics of most regions strongly correlated. Radial distribution functions calculated for both bOcn and tOcn show long-range ordering of the calcium ion distribution around the carboxylated glutamate (γGlu) residues, likely playing an important role in promoting stability of these Ocns. Additionally, the same calcium ions are observed to coordinate with neighboring γGlu, better shielding their negative charges and in turn stabilizing these systems more than do the singly coordinating calcium ions observed in the case of nOcn. bOcn is also found to exhibit a more helical C-terminal structure, that has been shown to activate its cellular receptor GPRC6A, highlighting the allosteric role of Ocn carboxylation in modulating the stability and binding potential of the active C-terminal.
CONCLUSIONS
The carboxylation status of Ocn as well and its calcium coordination appear to have a direct influence on Ocn structure and dynamics, possibly leading to the known differences in Ocn biological function.
GENERAL SIGNIFICANCE
Modification of Ocn sequence or its carboxylation state may provide the blueprint for developing high-affinity peptides targeting its cellular receptor GPRC6A, with therapeutic potential for treatment of metabolic disorders.
Topics: Amino Acid Sequence; Animals; Calcium; Carboxylic Acids; Glutamic Acid; Humans; Molecular Dynamics Simulation; Osteocalcin; Protein Conformation; Protein Stability
PubMed: 33340588
DOI: 10.1016/j.bbagen.2020.129809 -
Annals of Clinical Biochemistry Jul 2000
Review
Topics: Bone and Bones; Chemistry, Clinical; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hyperthyroidism; Hypothyroidism; Menopause; Osteitis Deformans; Osteocalcin; Osteomalacia; Osteoporosis; Reference Values; Reproducibility of Results
PubMed: 10902858
DOI: 10.1177/000456320003700402 -
Hormone and Metabolic Research =... Oct 2015Studies on the association between serum total osteocalcin level and type 2 diabetes mellitus (T2DM) had reported controversial results. The aim of this study was to... (Meta-Analysis)
Meta-Analysis Review
Studies on the association between serum total osteocalcin level and type 2 diabetes mellitus (T2DM) had reported controversial results. The aim of this study was to comprehensively assess this association through a meta-analysis. Eligible articles were identified in electronic databases from their inception through May 1, 2015. To assess the relationship between serum total osteocalcin and T2DM, a meta-analysis was performed to determine whether total osteocalcin differed obviously between individuals with and without T2DM, and whether serum total osteocalcin level was associated with the risk of T2DM. The standardized mean difference (SMD) and their 95% confidence intervals (95% CIs) for total osteocalcin between individuals with and without T2DM, and pooled odds ratios (ORs) and their 95% CI for the T2DM risk were calculated by meta-analysis. Twenty-four papers fulfilled the inclusion criteria. From the pooled data, the total osteocalcin level was significantly lower among T2DM patients than controls (SMD: - 2.87; 95% CI-3.76 to - 1.98; p<0.00001), and high total osteocalcin level was significantly and independently associated with decreased risk of T2DM (OR=0.70, 95% CI 0.56-0.88; p=0.002). There was no evidence for publication bias. Serum total osteocalcin level is significantly lower in T2DM patients than controls, and total osteocalcin is inversely associated with the development of T2DM.
Topics: Aged; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Osteocalcin; Publication Bias
PubMed: 26372899
DOI: 10.1055/s-0035-1564134