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Calcified Tissue International Feb 2023There exists a marked circadian variation for several bone markers (BM), which is influenced by endogenous as well as exogenous factors including hormones, physical... (Review)
Review
There exists a marked circadian variation for several bone markers (BM), which is influenced by endogenous as well as exogenous factors including hormones, physical activity, and fasting. Consequently, was the aim of this review to provide an overview of the knowledge of the circadian variation of BM and which factors influence this rhythmicity. A systematic search of PubMed was performed for studies evaluating the circadian variation of BM and which factors influence this rhythmicity. The studies were screened for eligibility by a set of predetermined criteria including a list of relevant BM and a minimum study duration of 24 h with at least 3 blood samples of which two should be at least 6 h apart. In total were 29 papers included. There exists a marked circadian variation for most BM including Carboxy-terminal Cross-Linked Telopeptide of Type I Collagen (CTX) and osteocalcin (OC) with nighttime or early morning peak. Pro-collagen Type I N-terminal Propeptide (PINP) and PTH also showed circadian rhythm but with less amplitude. The inter-osteoblast-osteoclast regulatory markers such as OPG, RANKL, FGF23, and sclerostin showed no circadian rhythm. The markers were differently affected by exogenous factors like fasting, which greatly reduced the circadian variation of CTX but did not affect PINP or OC. The marked circadian variation and the factors which influence the rhythmicity, e.g., fasting are of great consequence when measuring BM. To reduce variation and heighten validity should circadian variation and fasting be kept in mind when measuring BM.
Topics: Circadian Rhythm; Bone and Bones; Collagen Type I; Biomarkers; Osteocalcin
PubMed: 35305134
DOI: 10.1007/s00223-022-00965-1 -
The Journal of Clinical Investigation Feb 2022Osteocalcin is a hormone produced in bones by osteoblasts during bone formation. Numerous studies have demonstrated that adrenal gland-derived glucocorticoids inhibit...
Osteocalcin is a hormone produced in bones by osteoblasts during bone formation. Numerous studies have demonstrated that adrenal gland-derived glucocorticoids inhibit osteocalcin production, which can ultimately cause deleterious bones loss. This loss establishes a unidirectional endocrine relationship between the adrenal glands and bone, however, whether osteocalcin reciprocally regulates glucocorticoid secretion remains unclear. In this issue of the JCI, Yadav and colleagues address how bone-derived osteocalcin influences adrenal organogenesis and function. Using a large variety of animal models, the authors established that embryonic osteocalcin signaling, specifically through the GPR158 receptor, regulates postnatal adrenal steroid concentrations throughout life. This work has translational potential, and we await future investigations that determine whether modulating osteocalcin levels could promote endogenous adrenocortical function in adrenocortical hypoplasia and glucocorticoid deficiency.
Topics: Animals; Bone and Bones; Glucocorticoids; Osteoblasts; Osteocalcin; Osteogenesis
PubMed: 35166237
DOI: 10.1172/JCI157200 -
Metabolic Syndrome and Related Disorders Feb 2022The effect of diabetic polyneuropathy (DPN) and autonomic neuropathy (AN) on bone turnover in type 2 diabetes mellitus (DM) is uncertain due to the lack of data. In...
The effect of diabetic polyneuropathy (DPN) and autonomic neuropathy (AN) on bone turnover in type 2 diabetes mellitus (DM) is uncertain due to the lack of data. In this study, we tried to determine the effect of DPN and AN on bone metabolism. The study included patients with type 2 DM (aged 18-80 years) and age-matched healthy individuals who presented to the Departments of Metabolism and Diabetes, Geriatrics, and General Internal Medicine, Cerrahpaşa Medical School, Istanbul University. The patients were examined to find out whether they had AN, and neuropathy scores were recorded by exploring peripheral neuropathy. Bone mineral density was measured by dual-energy X-ray (DXA). Demographic characteristics, the presence of microvascular complications, and biochemical data were obtained from patients' files. Serum cross-linked C-telopeptide (Ctx), osteocalcin, and bone-specific alkaline phosphatase (B-ALP) were analyzed. The study comprised a total of 64 patients: 23 had type 2 DM and osteoporosis (OP) (duration of diabetes 10.1 ± 7 years; mean age 63 ± 9.1 years; female/male 18/5; Group 1), 41 had type 2 DM and non-OP (duration of diabetes 10.3 ± 7.6 years; mean age 58 ± 7.4 years; female/male 30/11; Group 2), and 26 healthy volunteers made up the control group (mean age 62 ± 11.9 years; female/male 14/12; Group 3). The bone turnover parameters were lower in type 2 DM individuals. The levels of osteocalcin (13.3 ± 5.2 ng/mL) and B-ALP (44.7 ± 10.9 IU/L) in patients with type 2 DM were lower than those of healthy subjects: osteocalcin (20.6 ± 10 ng/mL) and B-ALP (111 ± 31.4 IU/L; = 0.001 and = 0.000, respectively). Ctx levels (193.5 ± 49.3; 207.6 ± 40 ng/mL) were recorded to be similar ( = 0.2). AN was also noted as a risk factor for OP. For patients without AN, the likelihood of developing OP (odds ratio) was 0.7. The corresponding ratio for patients with AN was 9.3. Among the independent variables, the neuropathy score was determined to have an impact on bone turnover. AN was identified to be a significant risk factor for OP.
Topics: Aged; Female; Humans; Male; Middle Aged; Biomarkers; Bone Density; Bone Remodeling; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Osteocalcin; Osteoporosis
PubMed: 34818066
DOI: 10.1089/met.2021.0028 -
Archives of Osteoporosis Sep 2020Osteocalcin, the osteoblast-derived protein, has been shown to be modulated in patients with problematic glucose metabolism. Our systematic review and meta-analysis... (Meta-Analysis)
Meta-Analysis
UNLABELLED
Osteocalcin, the osteoblast-derived protein, has been shown to be modulated in patients with problematic glucose metabolism. Our systematic review and meta-analysis found that in humans, higher blood osteocalcin level is associated with lower body indices of fat.
PURPOSE/INTRODUCTION
Osteocalcin (OC) was found to be inversely correlated with measures of glucose and energy metabolism, with some groups suggesting the undercarboxylated form (ucOC) to be metabolically active, although the link is not clear, especially in humans. Given obesity is a major risk factor for metabolic disorders, we aimed to assess the correlation between OC and two measures of body weight: body mass index (BMI) and percentage body fat (%BF).
METHODS
MEDLINE and EMBASE were searched to identify observational studies in adult populations that reported the crude correlation coefficients (r) between OC and BMI and %BF. Pool r were obtained using random-effects models.
RESULTS
Fifty-one publications were included in this analysis. Both total OC (TOC) (pooled r = - 0.151, 95% CI - 0.17, - 0.130; I = 52%) and ucOC (pooled r = - 0.060, 95% CI - 0.103, - 0.016; I = 54%) were inversely correlated with BMI. The pooled r between TOC and BMI in Caucasian-and-other-regions (r = - 0.187) were stronger than those in Asian populations (r = - 0.126; intra-group p = 0.002; R = 0.21). The mean/median BMI of the reported cohort was the major contributor to between-study heterogeneity in correlation between TOC/ucOC and BMI (R = 0.28 and 0.77, respectively). Both TOC and ucOC were also inversely correlated with %BF (TOC: pooled r = - 0.185, 95% CI - 0.257 to - 0.112; ucOC: pooled r = - 0.181, 95% CI - 0.258 to - 0.101).
CONCLUSION
Higher OC and ucOC were correlated with lower BMI and %BF. The inverse correlations between TOC/ucOC and BMI appear to be affected by ethnicity and obesity status.
Topics: Adiposity; Adult; Body Mass Index; Body Weight; Humans; Obesity; Observational Studies as Topic; Osteocalcin
PubMed: 32945990
DOI: 10.1007/s11657-020-00812-6 -
Bone Jan 2020Osteocalcin (OC), an osteoblast-specific secreted protein expressed by mature osteoblasts, is used in clinical practice and in research as a marker of bone turnover. The...
PURPOSE
Osteocalcin (OC), an osteoblast-specific secreted protein expressed by mature osteoblasts, is used in clinical practice and in research as a marker of bone turnover. The carboxylated (cOC) and undercarboxylated (ucOC) forms may have a different biological function but age-specific reference ranges for these components are not established. Given the different physiological roles, development of reference ranges may help to identify people at risk for bone disease.
METHODS
Blood was collected in the morning after an overnight fast from 236 adult men (18 to 92 years old) free of diabetes, antiresorptive, warfarin or glucocorticoid use. Serum was analyzed for total osteocalcin (tOC) and the ucOC fraction using the hydroxyapatite binding method. cOC, ucOC/tOC and cOC/tOC ratios were calculated. Reference intervals were established by polynomial quantile regression analysis.
RESULTS
The normal ranges for young men (≤30 years) were: tOC 17.9-56.8 ng/mL, ucOC 7.1-22.0 ng/mL, cOC 8.51-40.3 ng/mL (2.5th to 97.5th quantiles). Aging was associated with a "U" shaped pattern for tOC, cOC and ucOC levels. ucOC/tOC ratio was higher, while cOC/tOC ratio was lower in men of advanced age. Age explained ∼31%, while body mass index explained ∼4%, of the variance in the ratios.
CONCLUSIONS
We have defined normal reference ranges for the OC forms in Australian men and demonstrated that the OC ratios may be better measures, than the absolute values, to identify the age-related changes on OC in men. These ratios may be incorporated into future research and clinical trials, and their associations with prediction of events, such as fracture or diabetes risk, should be determined.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Australia; Biomarkers; Bone Remodeling; Humans; Longevity; Male; Middle Aged; Osteocalcin; Young Adult
PubMed: 31622778
DOI: 10.1016/j.bone.2019.115085 -
Clinical Oral Investigations Apr 2023The aim of this in vitro study is to evaluate the effect of antioxidant lycopene on human osteoblasts.
OBJECTIVE
The aim of this in vitro study is to evaluate the effect of antioxidant lycopene on human osteoblasts.
MATERIAL AND METHOD
The human osteoblast cell line (CRL-11372) was obtained from the American Type Culture Collection (ATCC Manassas, Va) and grown in Dulbecco's Modified Eagle's medium (DMEM) supplemented with 10% fetal calf serum (FCS), penicillin (100 U/ml), and streptomycin (100 mg/ ml) at 37 °C in a humidified atmosphere of 5% CO and 95% air. The effective dose of lycopene was determined by MTT assay and a real-time cell analysis (RTCA) system. Proliferative effects were analyzed by in vitro wound healing model. Gene expressions of type 1 collagen (COL1A1), osteocalcin (OCN), and growth differentiation factor-5 (GDF-5) were measured by quantitative real-time polymerase chain reaction (qRT-PCR) at 72 h. Statistical differences between test groups were analyzed with a one-way ANOVA test.
RESULTS
MTT assay showed that the doses between 10 and 1 µmol of lycopene had dose-dependent proliferative effects. The doses between 10 and 10 µmol were most effective at 72 h. Lycopene accelerates the healing rate by increasing osteoblast proliferation.
CONCLUSION
Results suggested that lycopene had proliferative effects on human osteoblasts, which may help to increase bone regeneration, and thus, it can be useful in tissue engineering procedures.
CLINICAL RELEVANCE
By the help of antioxidants like lycopene capacity, velocity and quality of new bone forming may be increased in periodontal and dental implant treatments.
Topics: Humans; Antioxidants; Lycopene; Osteoblasts; Cell Line; Osteocalcin; Cell Proliferation; Cell Differentiation; Cells, Cultured
PubMed: 36416948
DOI: 10.1007/s00784-022-04789-z -
Nephrology, Dialysis, Transplantation :... Feb 2023Vitamin K activates matrix Gla protein (MGP), a key inhibitor of vascular calcification. There is a high prevalence of sub-clinical vitamin K deficiency in patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
Inhibit progression of coronary artery calcification with vitamin K in hemodialysis patients (the iPACK-HD study): a randomized, placebo-controlled multi-center, pilot trial.
BACKGROUND
Vitamin K activates matrix Gla protein (MGP), a key inhibitor of vascular calcification. There is a high prevalence of sub-clinical vitamin K deficiency in patients with end-stage kidney disease.
METHODS
A parallel randomized placebo-controlled pilot trial was designed to determine whether 10 mg of phylloquinone thrice weekly versus placebo modifies coronary artery calcification progression over 12 months in patients requiring hemodialysis with a coronary artery calcium score (CAC) ≥30 Agatston Units (ClinicalTrials.gov identifier NCT01528800). The primary outcome was feasibility (recruitment rate, compliance with study medication, study completion and adherence overall to study protocol). CAC score was used to assess calcification at baseline and 12 months. Secondary objectives were to explore the impact of phylloquinone on vitamin K-related biomarkers (phylloquinone, dephospho-uncarboxylated MGP and the Gla-osteocalcin to Glu-osteocalcin ratio) and events of clinical interest.
RESULTS
A total of 86 patients with a CAC score ≥30 Agatston Units were randomized to either 10 mg of phylloquinone or a matching placebo three times per week. In all, 69 participants (80%) completed the trial. Recruitment rate (4.4 participants/month) and medication compliance (96%) met pre-defined feasibility criteria of ≥4.17 and ≥90%, respectively. Patients randomized to phylloquinone for 12 months had significantly reduced levels of dephospho-uncarboxylated MGP (86% reduction) and increased levels of phylloquinone and Gla-osteocalcin to Glu-osteocalcin ratio compared with placebo. There was no difference in the absolute or relative progression of coronary artery calcification between groups.
CONCLUSION
We demonstrated that phylloquinone treatment improves vitamin K status and that a fully powered randomized trial may be feasible.
Topics: Humans; Vitamin K; Vitamin K 1; Osteocalcin; Pilot Projects; Coronary Artery Disease; Vascular Calcification; Calcium-Binding Proteins; Extracellular Matrix Proteins; Renal Dialysis; Vitamin K 2
PubMed: 35641194
DOI: 10.1093/ndt/gfac191 -
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 -
Biological Trace Element Research Jan 2020The gap junction protein plays an important role in the bone formation and alteration of these proteins leading to cause bone development. Aim to determine the effects...
The gap junction protein plays an important role in the bone formation and alteration of these proteins leading to cause bone development. Aim to determine the effects of different concentration of fluoride on gap-junctional intercellular communication (GJIC) related genes and proteins in the rats' osteoblast cells. We treated the osteoblast cells with various concentrations (0, 0.01, 0.1, 0.5, and 1.0 mM) NaF for 24 and 72 h. We used the scrape loading and dye transfer technique to research the intracellular connectivity. Moreover, the mRNA expression levels of connexin 43 (Cx43), connexin45 (Cx45), collagen I, and osteocalcin (OCN) were analyzed by qRT-PCR, the protein expression levels of connexin43 (Cx43) were analyzed by western blotting and immunofluorescence. Our results suggested that the osteoblast proliferations were decreased in the 0.5 and 1 mM NaF groups, after 24 and 72 treatments. The scrape loading and dye transfer experiment showed that the GJIC were increased in the 0.01 mM NaF group and decreased in the 0.5 and 1 mM NaF groups. In addition, the mRNA expressions of Cx43, Cx45, and OCN, and the protein expressions of Cx43 were increased in the 0.01 mM NaF group and decreased in the 0.5 and 1 mM NaF groups. In summary, these results suggest that the low concentration NaF is good for the GJIC, but the high concentration NaF damages the GJIC.
Topics: Animals; Cell Communication; Cells, Cultured; Connexin 43; Connexins; Fluorides; Gap Junctions; Gene Expression Regulation; Osteoblasts; Osteocalcin; Rats
PubMed: 30887282
DOI: 10.1007/s12011-019-01692-9 -
Scientific Reports Sep 2022Fracture nonunion is a common and challenging complication. Although direct current stimulation has been suggested to promote fracture healing, differences in cell...
Fracture nonunion is a common and challenging complication. Although direct current stimulation has been suggested to promote fracture healing, differences in cell density near the positive and negative electrodes have been reported during direct current stimulation. This study aimed to explore the effects of these differences on osteoblast proliferation and fracture healing. MC3T3-E1 cells were stimulated by positive and negative charges to observe cell proliferation, apoptosis, and osteogenic factor expression in vitro, while positive and negative charges were connected to the Kirschner wires of the fractures in an in vivo double-toe fracture model in New Zealand white rabbits and fracture healing was assessed in digital radiography (DR) examinations performed on days 1, 15, 30. Bone tissue samples of all rabbits were analysed histologically after the last examination. The results showed that in comparison with the control group, after DC stimulation, the number of cells near the positive electrode decreased significantly (P < 0.05), apoptosis increased (P < 0.05), the expression of osteocalcin, osteoblast-specific genes, and osteonectin decreased significantly near the positive electrode (P < 0.05) and increased significantly at the negative electrode (P < 0.05). The fracture at the positive electrode junction of New Zealand white rabbits did not heal. Histomorphological analysis showed more bone trabeculae and calcified bone in the bone tissue sections of the control group and the negative electrode group than in the positive electrode group. The bone trabeculae were thick and showed good connections. However, positive charge inhibited osteoblast proliferation and a positive charge at fracture sites did not favour fracture healing. Thus, a positive charge near the fracture site may be a reason for fracture nonunion.
Topics: Animals; Fracture Healing; Fractures, Bone; Fractures, Ununited; Osteocalcin; Osteogenesis; Osteonectin; Rabbits
PubMed: 36151271
DOI: 10.1038/s41598-022-20153-3