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Frontiers in Endocrinology 2022Osteoblasts are discovered to secrete hormones with endocrine effects on metabolism, and osteocalcin (OC) is the most abundant non-collagenous protein in bone. We...
OBJECTIVE
Osteoblasts are discovered to secrete hormones with endocrine effects on metabolism, and osteocalcin (OC) is the most abundant non-collagenous protein in bone. We investigate the relationship between serum OC levels and glycolipid metabolism and muscle function in children with osteogenesis imperfecta (OI).
METHODS
A total of 225 children with OI and 80 healthy controls matched in age and gender were included in this single center study. Serum levels of fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), low- and high-density lipoprotein cholesterol (LDL-C, HDL-C) were measured by automated analyzers. Serum levels of fasting insulin (FINS) were measured using an automated electrochemiluminescence system. Serum levels of OC and undercarboxylated osteocalcin (ucOC) were measured by enzyme-linked immunosorbent assay. Grip strength and timed-up-and-go (TUG) test were measured. Bone mineral density (BMD) and body composition were measured using dual-energy X-ray absorptiometry.
RESULTS
OI patients had significantly higher body mass index (BMI), FBG, and HOMA-IR, but lower HDL-C levels, lower grip strength and longer TUG than control group (all <0.05). Serum OC, ucOC levels, and ucOC/OC in OI type III patients were significantly lower than those in OI patients with type I and IV. Serum levels of OC, ucOC, and ucOC/OC were negatively correlated to BMI, FBG, insulin levels, and HOMA-IR (all <0.05). The ratio of ucOC/OC was positively correlated to grip strength (r=0.512, =0.036), lean mass percentage (%LM) of the total body and limbs, and negatively correlated to fat mass percentage (%FM) of the total body, %FM and fat mass index (FMI) of the trunk (all <0.05).
CONCLUSIONS
Obesity, glucolipid metabolic abnormalities, and reduced grip strength were common in children with OI. Circulating osteocalcin and ucOC may play an important role in the regulation of glucose metabolism, as well as the muscle function of children with OI.
Topics: Child; Cholesterol; Glycolipids; Humans; Insulin; Muscles; Osteocalcin; Osteogenesis Imperfecta
PubMed: 35983511
DOI: 10.3389/fendo.2022.898645 -
Biointerphases May 2017Adsorption isotherms, circular dichroism (CD) spectroscopy, x-ray photoelectron spectroscopy (XPS), and time-of-flight secondary ion mass spectrometry (ToF-SIMS) were...
Adsorption isotherms, circular dichroism (CD) spectroscopy, x-ray photoelectron spectroscopy (XPS), and time-of-flight secondary ion mass spectrometry (ToF-SIMS) were used to investigate the adsorption of human osteocalcin (hOC) and decarboxylated (i.e., Gla converted back to Glu) hOC (dhOC) onto various calcium phosphate surfaces as well as silica surfaces. The adsorption isotherms and XPS nitrogen signals were used to track the amount of adsorbed hOC and dhOC. The intensities of key ToF-SIMS amino acid fragments were used to assess changes in the structure of adsorbed hOC and dhOC. CD spectra were used to investigate the secondary structure of OC. The largest differences were observed when the proteins were adsorbed onto silica versus calcium phosphate surfaces. Similar amounts (3-4 at. % N) of hOC and dhOC were adsorbed onto the silica surface. Higher amounts of hOC and dhOC were adsorbed on all the calcium phosphate surfaces. The ToF-SIMS data showed that the intensity of the Cys amino acid fragment, normalized to intensity of all amino acid fragments, was significantly higher (∼×10) when the proteins were adsorbed onto silica. Since in the native OC structure the cysteines are located in the center of three α-helices, this indicates both hOC and dhOC are more denatured on the silica surface. As hOC and dhOC denature upon adsorption to the silica surface, the cysteines become more exposed and are more readily detected by ToF-SIMS. No significant differences were detected between hOC and dhOC adsorbed onto the silica surface, but small differences were observed between hOC and dhOC adsorbed onto the calcium phosphate surfaces. In the OC structure, the α-3 helix is located above the α-1 and α-2 helices. Small differences in the ToF-SIMS intensities from amino acid fragments characteristic of each helical unit (Asn for α-1; His for α-2; and Phe for α-3) suggests either slight changes in the orientation or a slight uncovering of the α-1 and α-2 for adsorbed dhOC. XPS showed that similar amounts of hOC and dhOC were absorbed onto hydroxyapaptite and octacalcium phosphate surfaces, but ToF-SIMS detected some small differences in the amino acid fragment intensities on these surfaces for adsorbed hOC and dhOC.
Topics: Calcium Phosphates; Humans; Osteocalcin; Photoelectron Spectroscopy; Protein Structure, Secondary; Silicon Dioxide; Spectrometry, Mass, Secondary Ion; Surface Properties
PubMed: 28521505
DOI: 10.1116/1.4983407 -
Lipids in Health and Disease Aug 2020Recent studies have investigated the circulating adipocyte fatty acid binding protein (FABP4), nesfatin-1, and osteocalcin (OC) concentrations in women diagnosed with... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Recent studies have investigated the circulating adipocyte fatty acid binding protein (FABP4), nesfatin-1, and osteocalcin (OC) concentrations in women diagnosed with gestational diabetes mellitus (GDM), but the findings prove to be conflicting. The objective of this research was to systematically assess the relationship of circulating levels of above adipokines with GDM.
METHODS
Pubmed, Embase, Web of Science, Cochrane library, OVID, and Scopus were performed to locate articles published up to January 31, 2020. Pooled standard mean differences (SMDs) with 95% confidence intervals (CIs), and 95% predictive intervals (PIs) were calculated by random-effects models to compare levels of adipokines between GDM cases and control groups. Cumulative and single-arm meta-analyses were also performed.
RESULTS
Thirty-one studies comprising 4590 participants were included. No significant differences were found between GDM women and healthy controls in circulating nesfatin-1 levels (4.56 vs. 5.02 ng/mL; SMD = - 0.11, 95% CI -0.61-0.38, 95% PI -1.63-1.41). Nevertheless, circulating FABP4 and OC levels observed in GDM women outnumbered normal controls (FABP4, 23.68 vs. 16.04 ng/mL; SMD = 2.99, 95% CI 2.28-3.69, 95% PI 0.28-5.71; OC, 52.34 vs. 51.04 ng/mL; SMD = 0.68, 95% CI 0.31-1.05, 95% PI -0.48-1.84). The cumulative meta-analysis showed that the SMDs of circulating FABP4 and OC levels had stabilized between the two groups.
CONCLUSIONS
Elevated circulating FABP4 and OC levels were observed in GDM women, but nesfatin-1 levels did not change, the PI of OC crossed the no-effect threshold. The results suggested that FABP4 is more suitable as a biomarker of GDM compared to OC in a future study, which is useful in identifying pregnant women who are likely to develop GDM and providing prompt management strategies.
Topics: Diabetes, Gestational; Fatty Acid-Binding Proteins; Female; Humans; Nucleobindins; Osteocalcin; Pregnancy
PubMed: 32861247
DOI: 10.1186/s12944-020-01365-w -
Cardiovascular Diabetology Jun 2022The association between osteocalcin and mortality has been scantly studied. We aimed to investigate the association between osteocalcin along with its trajectories and...
BACKGROUND
The association between osteocalcin and mortality has been scantly studied. We aimed to investigate the association between osteocalcin along with its trajectories and mortality based on long-term longitudinal data.
METHODS
We performed a retrospective cohort study of 9413 type 2 diabetic patients with at least three measurements of total serum osteocalcin within 3 years since their first inpatient diagnosis of type 2 diabetes. Baseline, mean values of osteocalcin levels and their trajectories were used as exposures. A multivariable-adjusted Cox proportional hazards model was used to estimate the association of osteocalcin levels and their trajectories with mortality.
RESULTS
During a mean follow-up of 5.37 years, 1638 patients died, of whom 588 were due to cardiovascular events. Multivariable-adjusted hazard ratios (HRs) across quintiles of baseline osteocalcin levels were 2.88 (95% confidence interval (CI) 2.42-3.42), 1.65 (95% CI 1.37-1.99), 1.17 (95% CI 0.96-1.42), 1.00, and 1.92 (95% CI 1.60-2.30) for all-cause mortality, and 3.52 (95% CI 2.63-4.71), 2.00 (95% CI 1.46-2.73), 1.03 (95% CI 0.72-1.47), 1.00, 1.67 (95% CI 1.21-2.31) for CVD mortality, respectively. When we used the mean values of osteocalcin as the exposure, U-shaped associations were also found. These U-shaped associations were consistent among patients of different baseline characteristics. Patients with a stable or even increasing trajectory of osteocalcin may have a lower risk of both all-cause and CVD mortality.
CONCLUSIONS
A U-shape association between baseline osteocalcin and mortality was observed among patients with type 2 diabetes. Patients with lower levels of serum osteocalcin during follow-ups had higher risks for all-cause and cardiovascular mortality.
Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Mortality; Osteocalcin; Retrospective Studies; Risk Factors
PubMed: 35681236
DOI: 10.1186/s12933-022-01539-z -
Scientific Reports Apr 2019The G protein-coupled receptor class C, group 6, subtype A (GPRC6A) is suggested to have a physiological function in glucose and bone metabolism, although the precise...
The G protein-coupled receptor class C, group 6, subtype A (GPRC6A) is suggested to have a physiological function in glucose and bone metabolism, although the precise role lacks consensus due to varying findings in different knockout (KO) mouse models and inconsistent findings on the role of osteocalcin, a proposed GPRC6A agonist. We have further characterized a full locus GPRC6A KO model with respect to energy metabolism, including a long-term high-dose glucocorticoid metabolic challenge. Additionally, we analyzed the microarchitecture of tibiae from young, middle-aged and aged GPRC6A KO mice and wildtype (WT) littermates. Compared to WT, vehicle-treated KO mice presented with normal body composition, unaltered insulin sensitivity and basal serum insulin and glucose levels. Corticosterone (CS) treatment resulted in insulin resistance, abnormal fat accrual, loss of lean mass and suppression of serum osteocalcin levels in both genotypes. Interestingly, serum osteocalcin and skeletal osteocalcin mRNA levels were significantly lower in vehicle-treated GPRC6A KO mice compared to WT animals. However, WT and KO age groups did not differ in long bone mass and structure assessed by micro-computed tomography. We conclude that GPRC6A is not involved in glucose metabolism under normal physiological conditions, nor does it mediate glucocorticoid-induced dysmetabolism in mice. Moreover, GPRC6A does not appear to possess a direct, non-compensable role in long bone microarchitecture under standard conditions.
Topics: Animals; Blood Glucose; Body Composition; Cancellous Bone; Cortical Bone; Gene Expression Regulation; Genetic Loci; Genotype; Homeostasis; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteocalcin; RNA, Messenger; Receptors, G-Protein-Coupled; Tibia
PubMed: 30979912
DOI: 10.1038/s41598-019-41921-8 -
Advances in Nutrition (Bethesda, Md.) Mar 2012Seventeen vitamin K-dependent proteins have been identified to date of which several are involved in regulating soft-tissue calcification. Osteocalcin, matrix Gla... (Review)
Review
Seventeen vitamin K-dependent proteins have been identified to date of which several are involved in regulating soft-tissue calcification. Osteocalcin, matrix Gla protein (MGP), and possibly Gla-rich protein are all inhibitors of soft-tissue calcification and need vitamin K-dependent carboxylation for activity. A common characteristic is their low molecular weight, and it has been postulated that their small size is essential for calcification inhibition within tissues. MGP is synthesized by vascular smooth muscle cells and is the most important inhibitor of arterial mineralization currently known. Remarkably, the extrahepatic Gla proteins mentioned are only partly carboxylated in the healthy adult population, suggesting vitamin K insufficiency. Because carboxylation of the most essential Gla proteins is localized in the liver and that of the less essential Gla proteins in the extrahepatic tissues, a transport system has evolved ensuring preferential distribution of dietary vitamin K to the liver when vitamin K is limiting. This is why the first signs of vitamin K insufficiency are seen as undercarboxylation of the extrahepatic Gla proteins. New conformation-specific assays for circulating uncarboxylated MGP were developed; an assay for desphospho-uncarboxylated matrix Gla protein and another assay for total uncarboxylated matrix Gla protein. Circulating desphospho-uncarboxylated matrix Gla protein was found to be predictive of cardiovascular risk and mortality, whereas circulating total uncarboxylated matrix Gla protein was associated with the extent of prevalent arterial calcification. Vitamin K intervention studies have shown that MGP carboxylation can be increased dose dependently, but thus far only 1 study with clinical endpoints has been completed. This study showed maintenance of vascular elasticity during a 3-y supplementation period, with a parallel 12% loss of elasticity in the placebo group. More studies, both in healthy subjects and in patients at risk of vascular calcification, are required before conclusions can be drawn.
Topics: Animals; Calcification, Physiologic; Calcinosis; Calcium-Binding Proteins; Extracellular Matrix Proteins; Humans; Liver; Muscle, Smooth, Vascular; Osteocalcin; Vitamin K; Matrix Gla Protein
PubMed: 22516724
DOI: 10.3945/an.111.001628 -
Frontiers in Endocrinology 2021Bone and skeletal muscle represent a single functional unit. We cross-sectionally investigated body composition, risk of fall and circulating osteocalcin (OC) isoforms...
BACKGROUND
Bone and skeletal muscle represent a single functional unit. We cross-sectionally investigated body composition, risk of fall and circulating osteocalcin (OC) isoforms in osteoporotic postmenopausal women to test the hypothesis of an involvement of OC in the bone-muscle crosstalk.
MATERIALS AND METHODS
Twenty-nine non-diabetic, non-obese, postmenopausal osteoporotic women (age 72.4 ± 6.8 years; BMI 23.0 ± 3.3 kg/m) underwent to: 1) fasting blood sampling for biochemical and hormone assays, including carboxylated (cOC) and uncarboxylated (uOC) osteocalcin; 2) whole-body dual energy X-ray absorptiometry (DXA) to assess total and regional body composition; 3) magnetic resonance imaging to determine cross-sectional muscle area (CSA) and intermuscular adipose tissue (IMAT) of thigh muscles; 4) risk of fall assessment through the OAK system.
RESULTS
Appendicular skeletal muscle index (ASMMI) was low in 45% of patients. Forty percent got a low OAK score, consistent with moderate-severe risk of fall, which was predicted by low legs lean mass and increased total fat mass. Circulating cOC levels showed significantly correlated with βCTx-I, lean mass parameters including IMAT, and OAK score. Fractured and unfractured women did not differ for any of the analyzed parameters, though cOC and uOC positively correlated with legs lean mass, OAK score and bone markers only in fractured women.
CONCLUSIONS
Data supported the relationship between OC and skeletal muscle mass and function in postmenopausal osteoporotic women. Serum cOC, but not uOC, emerges as mediator in the bone-muscle crosstalk. Circulating cOC and uOC levels may be differentially regulated in fractured and unfractured osteoporotic women, suggesting underlying differences in bone metabolism.
Topics: Accidental Falls; Aged; Aged, 80 and over; Biomarkers; Carboxylic Acids; Case-Control Studies; Cross-Sectional Studies; Female; Follow-Up Studies; Humans; Middle Aged; Muscle, Skeletal; Muscular Diseases; Osteocalcin; Osteoporosis, Postmenopausal; Prognosis; Protein Processing, Post-Translational; Risk Factors
PubMed: 34025583
DOI: 10.3389/fendo.2021.669704 -
Journal of Bone and Mineral Research :... Jun 2010Osteoporosis is a major health problem affecting more than 75 million people throughout Europe, the United States, and Japan. Epidemiologic studies have determined that...
Osteoporosis is a major health problem affecting more than 75 million people throughout Europe, the United States, and Japan. Epidemiologic studies have determined that both genetic and environmental factors contribute to the pathogenesis of osteoporosis. We have investigated the association between polymorphisms at the osteocalcin locus and variables linked to bone health. Osteocalcin provides a link between bone and energy metabolism, hence its potential importance as an osteoporosis candidate gene. In this study, we included a total of 996 women (all aged 75 years) from the Osteoporosis Prospective Risk Assessment (OPRA) cohort. We sequenced the osteocalcin gene along with flanking regions to search for novel coding polymorphisms. We also analyzed four polymorphisms selected from within and flanking regions of the osteocalcin gene to study their association with serum total osteocalcin levels (S-TotalOC), total-body (TB) bone mineral density (BMD), fracture, TB fat mass, and body mass index (BMI). The promoter polymorphism rs1800247 was significantly associated with S-TotalOC (p = .012) after controlling for BMI and TB BMD. The polymorphism rs1543297 was significantly associated with prospectively occurring fractures (p = .008). In a model taking into account rs1543297 and rs1800247, along with TB BMD, BMI, smoking, and S-TotalOC, the polymorphisms together were able to identify an additional 6% of women who sustained a fracture (p = .02). We found no association between the polymorphisms and TB BMD, BMI, or TB fat mass. In conclusion, polymorphisms in and around the osteocalcin locus are significantly associated with S-TotalOC and fracture. Genotyping at the osteocalcin locus could add valuable information in the identification of women at risk of osteoporosis.
Topics: Aged; Cohort Studies; Female; Fractures, Bone; Gene Frequency; Genotype; Humans; Logistic Models; Osteocalcin; Polymorphism, Single Nucleotide; Risk Factors; Sweden
PubMed: 20200947
DOI: 10.1002/jbmr.32 -
Progress in Orthodontics Oct 2017With change in concepts of growth determination methods, there is a surge in the measurement of biomarkers for appraisal of growth status. Osteocalcin is a bone-specific... (Comparative Study)
Comparative Study
BACKGROUND
With change in concepts of growth determination methods, there is a surge in the measurement of biomarkers for appraisal of growth status. Osteocalcin is a bone-specific protein and was observed to parallel the normal growth curve. Hence, the present study was intended to assess the levels of serum osteocalcin and serum insulin-like growth factor-1 (IGF-1) and compare them with cervical vertebral maturation index (CVMI) stages.
METHODS
The cross-sectional study was performed on 150 subjects (75 males and 75 females) in the age group of 8-20 years and segregated into six CVMI stages. Serum osteocalcin and IGF-1 were estimated by ELISA. Mann-Whitney U test was used to compare the mean ranks of serum osteocalcin and serum IGF-1 with different CVMI stages. Spearman correlation was performed to find association between serum osteocalcin and serum IGF-1 across six CVMI stages.
RESULTS
Peak serum IGF-1 levels were obtained at CVMI stages 4 and 3 for males and females, respectively, with insignificant difference between stages 3 and 4 in females. Peak serum osteocalcin levels were found at stage 5 and 3 for males and females with insignificant difference from other stages except stages 5 and 6 in males. A statistically significant correlation was seen between serum IGF-1 and serum osteocalcin across six CVMI stages (P < 0.01).
CONCLUSIONS
Osteocalcin followed IGF-1 across all CVMI stages but showed insignificant interstage differences.
Topics: Adolescent; Adult; Biomarkers; Cervical Vertebrae; Child; Female; Growth; Humans; Insulin-Like Growth Factor I; Male; Osteocalcin
PubMed: 28967046
DOI: 10.1186/s40510-017-0184-y -
Journal of Endocrinological... Jun 2022Osteocalcin (OC), an osteoblast-derived regulator of metabolic processes, and circulating early endothelial progenitor cells (EPC, CD34 - /CD133 + /KDR +)...
Osteocalcin-expressing endothelial progenitor cells and serum osteocalcin forms are independent biomarkers of coronary atherosclerotic disease severity in male and female patients.
PURPOSE
Osteocalcin (OC), an osteoblast-derived regulator of metabolic processes, and circulating early endothelial progenitor cells (EPC, CD34 - /CD133 + /KDR +) expressing OC (OC +) are potential candidates linking bone metabolism and the vasculature and might be involved in vascular atherosclerotic calcification. This study aimed at assessing the association of circulating levels of different OC forms and of EPCs count with disease severity in patients with documented coronary atherosclerosis (CAD).
METHODS
Patients (n = 59) undergoing coronary angiography were divided, according to stenosis severity, into (1) early coronary atherosclerosis (ECA) (n = 22), and (2) late coronary atherosclerosis (LCA) (n = 37). Total OC (TOC), carboxylated OC (cOC), undercarboxylated OC (unOC) were quantified by ELISA. EPC OC + count was assessed by flow cytometry.
RESULTS
EPC OC + counts showed significant differences between ECA and LCA groups. unOC and unOC/TOC ratio were inversely correlated with EPC OC + count. A significant decrease in TOC and unOC plasma levels was associated with higher cardiovascular risk factors (CVRFs) number. EPC OC + count was correlated with LDL-C, total cholesterol, and triglycerides, with a greater significance in the LCA group. No association between the different forms of circulating OC (TOC, ucOC, cOC) and severity of CAD was found.
CONCLUSION
This study showed a significant association between EPCs (CD34 - /CD133 + /KDR + /OC +), CAD severity and CVRFs, suggesting an active role for EPC OC + in the development of CAD. An inverse correlation between TOC, ucOC, and number of CVRFs was observed, suggesting that OC, regardless of its carboxylation status, may be developed as a further cardiovascular risk biomarker.
Topics: Antigens, CD34; Biomarkers; Coronary Artery Disease; Endothelial Progenitor Cells; Female; Humans; Male; Osteocalcin; Severity of Illness Index
PubMed: 35089541
DOI: 10.1007/s40618-022-01744-3