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PubMed2002

Osteocalcin and the hormonal, inflammatory and metabolic response to major orthopaedic surgery.

Plasma osteocalcin, a marker of osteoblastic activity, decreases after major abdominal and gynaecological surgery. Increased cortisol secretion and other hormonal and inflammatory components of the peri-operative stress response may play a role in mediating this response. We assessed the effects of three different anaesthetic techniques on peri-operative osteocalcin concentrations. Thirty-six female patients undergoing elective total hip replacement were randomly assigned to receive propofol, propofol plus 'three-in-one' block or etomidate as part of a general anaesthetic technique. We measured plasma osteocalcin and serum cortisol, bone specific alkaline phosphatase, interleukin-6, plasma epinephrine, norepinephrine, plasma glucose and cystatin C concentrations for up to 3 days after surgery. Etomidate successfully inhibited the cortisol response to surgery but plasma osteocalcin declined in all patients. This was accompanied by increased plasma catecholamines, interleukin-6 and glucose concentrations, and decreased cystatin C-values. Inhibition of the cortisol response to surgery failed to prevent a decrease in plasma osteocalcin concentrations after surgery, suggesting that other factors such as cytokines or catecholamines may play a significant role.

Aged↗
PubMed2000

Osteocalcin metabolism in the pulmonary circulation.

The aim of this study was to evaluate the role of the pulmonary vessel endothelium in the removal of circulating osteocalcin, by measuring the osteocalcin levels in serum from pulmonary and radial artery blood from 39 patients undergoing aorto-coronary bypass. Because of the discrepancies between methods of measurement, two methods were used. Significant differences were observed in group A (n = 18), tested with heterologous radioimmunoassay (2.85 +/- 0.67 microg l-1 in the pulmonary versus 2.69 +/- 0.67 microg l-1 in the radial artery serum, P<0.001) and in group B (n = 21), tested with a two-site immunoradiometric assay (5.22 +/- 1.46 versus 4.93 +/- 1.36 microg l-1, P<0.01). The percentage differences were -5.54 +/- 4.76% (P<0.001) in group A and -4.99 +/- 8.13% (P<0.01) in group B; the comparison between the percentage differences was not significant. These different osteocalcin concentrations between the two vascular compartments were considered a marker of osteocalcin degradation. Therefore, the study seems to demonstrate that, as well as kidney, liver and bone, the lung is a relevant site of osteocalcin catabolism. The proteolytic activity of pulmonary vessel endothelium seems to involve about 5% of the circulating peptide.

Aged↗
PubMed2005

Osteocalcin protein sequences of Neanderthals and modern primates.

We report here protein sequences of fossil hominids, from two Neanderthals dating to approximately 75,000 years old from Shanidar Cave in Iraq. These sequences, the oldest reported fossil primate protein sequences, are of bone osteocalcin, which was extracted and sequenced by using MALDI-TOF/TOF mass spectrometry. Through a combination of direct sequencing and peptide mass mapping, we determined that Neanderthals have an osteocalcin amino acid sequence that is identical to that of modern humans. We also report complete osteocalcin sequences for chimpanzee (Pan troglodytes) and gorilla (Gorilla gorilla gorilla) and a partial sequence for orangutan (Pongo pygmaeus), all of which are previously unreported. We found that the osteocalcin sequences of Neanderthals, modern human, chimpanzee, and orangutan are unusual among mammals in that the ninth amino acid is proline (Pro-9), whereas most species have hydroxyproline (Hyp-9). Posttranslational hydroxylation of Pro-9 in osteocalcin by prolyl-4-hydroxylase requires adequate concentrations of vitamin C (l-ascorbic acid), molecular O(2), Fe(2+), and 2-oxoglutarate, and also depends on enzyme recognition of the target proline substrate consensus sequence Leu-Gly-Ala-Pro-9-Ala-Pro-Tyr occurring in most mammals. In five species with Pro-9-Val-10, hydroxylation is blocked, whereas in gorilla there is a mixture of Pro-9 and Hyp-9. We suggest that the absence of hydroxylation of Pro-9 in Pan, Pongo, and Homo may reflect response to a selective pressure related to a decline in vitamin C in the diet during omnivorous dietary adaptation, either independently or through the common ancestor of these species.

Amino Acid Sequence↗
PubMed1997

A weak TATA box is a prerequisite for glucocorticoid-dependent repression of the osteocalcin gene.

The TATA box element is not only important for establishing basal levels of transcription, but it can also be used to modulate cell type or stage specific gene activity. In the case of the human osteocalcin gene, which is transcriptionally repressed by glucocorticoids, a specific binding element for the glucocorticoid receptor (GR) overlaps a noncanonical TATA box. In the present study, the relevance and function of the TATA element in glucocorticoid-mediated repression of the human osteocalcin gene was characterized. Mutating this noncanonical TATA box into a consensus TATA box within the context of the osteocalcin promoter greatly decreased hormone-dependent transcriptional repression by GR. TATA-binding protein (TBP) bound this mutated element much more strongly suggesting a physiologically relevant role for the weak osteocalcin TATA element in the regulation of this bone specific gene. The optimization of the putative transcription factor IIB recognition site did not affect the level of GR-mediated repression. Our results support a model wherein competitive DNA binding of GR and TBP for their overlapping sites explains conditional repression of the osteocalcin gene by glucocorticoids.

Binding, Competitive↗
PubMed2003

Lymphoid enhancer factor-1 and beta-catenin inhibit Runx2-dependent transcriptional activation of the osteocalcin promoter.

Functional control of the transcription factor Runx2 is crucial for normal bone formation. Runx2 is detectable throughout osteoblast development and maturation and temporally regulates several bone-specific genes. In this study, we identified a novel post-translational mechanism regulating Runx2-dependent activation of the osteocalcin promoter. A functional binding site for the high mobility group protein lymphoid enhancer-binding factor 1 (LEF1) was found adjacent to the proximal Runx2-binding site in the osteocalcin promoter. In transcription assays, LEF1 repressed Runx2-induced activation of the mouse osteocalcin 2 promoter in several osteoblast lineage cell lines. Mutations in the LEF1-binding site increased the basal activity of the osteocalcin promoter; however, the LEF1 recognition site in the osteocalcin promoter was surprisingly not required for LEF1 repression. A novel interaction between the DNA-binding domains of Runx2 and LEF1 was identified and found crucial for LEF1-mediated repression of Runx2. LEF1 is a nuclear effector of the Wnt/LRP5/beta-catenin signaling pathway, which is also essential for osteoblast proliferation and normal skeletal development. A constitutively active beta-catenin enhanced LEF1-dependent repression of Runx2. These data identify a novel mechanism of regulating Runx2 activity in osteoblasts and link Runx2 transcriptional activity to beta-catenin signaling.

3T3 Cells↗
PubMed1998

Diurnal rhythm of serum osteocalcin in normal children.

The aim of the present study was to assess diurnal levels of serum osteocalcin in normal children using a recently introduced fluoroimmunoassay (Pharmacia Osteocalcin CAP FEIA) measuring solely the intact peptide. Five girls and two boys aged 10.4-13.6 (mean 12.2) y were studied. Blood samples for determination of osteocalcin were collected every 2h throughout the day. A statistically significant rise in serum osteocalcin (F = 6.7, p < 0.001) with a peak at 08.00 h and a nadir lasting from 10.00 to 24.00 h was found. Trough and peak levels (at 16.00 and 08.00 h, respectively) were 41.6 +/- 6.8 and 66.0 +/- 10.5 microg l(-1) (mean +/- SEM). The circadian variation should be taken into consideration when single assessments of serum osteocalcin in children are performed.

Adolescent↗
PubMed2002

A novel cDNA transcript inversely regulated to osteocalcin in differentiating osteoblast-like cells.

In vitro MC3T3-E1 osteoblastic cells differentiate from a preosteoblastic to a mature osteoblastic phenotype constitutively expressing osteocalcin. For this process cell contacts seem to be an essential prerequisite. Using differential display of mRNA from subconfluent and confluent MC3T3-E1 cultures, we isolated and cloned a novel cDNA transcript, named Mc2, exhibiting an open reading frame of 162 bp and without extensive homologies to sequences in the EMBL database. The presence of the Mc2 mRNA was verified in primary mouse osteoblasts. Mc2 mRNA was upregulated during the transition of MC3T3-E1 cell cultures from subconfluence to confluence. In long-term cultures, Mc2 mRNA expression reached a maximum between days 8 and 12, and decreased again on day 21, when osteocalcin expression significantly increased. Treatment of these cells with by 3,3',5-triiodo-l-thyronine resulted in an inhibition of the culture time-dependent upregulation of Mc2 mRNA, whereby osteocalcin mRNA was highly expressed. This inverse regulation of Mc2 and osteocalcin mRNAs was also found in ROS 17/2.8 cells and in mouse bone marrow stromal cells. Transfection experiments showed that uncontrolled expression of a Mc2-GFP vector led to increased cell death in MC3T3-E1 cells. The transient upregulation of Mc2 mRNA in osteoblast-like cells and its interesting inverse regulation to osteocalcin suggest an important role in osteoblastic differentiation.

3T3 Cells↗
PubMed1995

Rat serum osteocalcin concentration is decreased by restriction of energy intake.

We studied the effects of energy restriction on serum osteocalcin concentration and bone formation rate in rats. The experiment was designed to achieve energy restriction by reducing the carbohydrate intake while providing identical quantities of protein, fat, vitamins and minerals. Energy intakes of three groups of post-weaning male rats were restricted by 20, 40 and 60% for 4 wk. Serum calcium, phosphorus, transthyretin, triiodothyronine (T3), thyroxine (T4), 1,25-dihydroxycholecalciferol, 25-hydroxycholecalciferol and immunoreactive parathyroid hormone (iPTH) concentrations were determined. Energy restriction (20, 40 and 60%) produced a significant and gradual drop of serum osteocalcin concentrations, although the serum concentrations of its key regulators, i.e., 1,25-dihydroxycholecalciferol and iPTH, were not significantly affected. On the contrary, serum concentrations of calcium, phosphorus, transthyretin, T3 and T4 were significantly lower in the energy-restricted groups. However, our results do not support their implication in the regulation of serum osteocalcin synthesis by energy intake. Serum osteocalcin concentration was positively correlated with bone mineral apposition (r = 0.50, P < 0.05) and bone mineralization (r = 0.50, P < 0.05) rates suggesting that its decrease resulted from a reduction of bone formation, and not from abnormal mineralization, because osteoid seam thickness was not modified. Energy intake seems to be an important determinant of serum osteocalcin concentration and bone formation; however, the exact mechanism underlying this regulation remains to be determined.

Animals↗
PubMed1989

Serum and synovial fluid osteocalcin (bone gla protein) levels in joint disease.

Osteocalcin (bone gla protein) is a sensitive marker of bone turnover in metabolic disease. Using a well characterized antiserum (R 102M) we have assayed serum and synovial fluid samples from patients with osteoarthritis (OA) and rheumatoid arthritis (RA) and related levels to serological and radiological markers of disease. There were 21 patients with RA (mean age 58.2 years, 15 F) and 33 with OA (mean age 69.2, 28 F). Paired serum and synovial fluids (SF) were available in 19 RA patients and 30 OA patients. Serum osteocalcin levels were related to age-/sex-matched normals and to a small group of elderly disease controls. Serum levels tended to be lower in RA than controls, but not significantly so: RA 5.56 (3.67); control 6.09 (2.54) ng/ml; expressed as mean (SD) and the mean serum/SF ratio was 0.88 (0.86). The results were much more variable in OA (mean serum osteocalcin 6.1 (3.9]. Elevated levels were mainly due to a small number of patients with a destructive form of OA and were higher than those with non-destructive OA (10.3 (3.5), n = 20, versus 3.83 (1.6), n = 10). Patients with non-destructive OA had a lower serum osteocalcin than age-/sex-matched normals. In this study, synovial fluid levels were usually less than serum concentrations, but in two RA and four OA patients the ratio was reversed, suggesting local production. Osteocalcin may be an important marker of bone activity in OA.

Adrenal Cortex Hormones↗
PubMed1992

Serum osteocalcin concentrations in patients with multiple myeloma--correlation with disease stage and survival.

Multiple myeloma affects bone, and enhanced bone resorption is a characteristic finding. In the present study the serum concentration of osteocalcin, serum bone gla-protein, which is a protein specific for bone turnover and reflects osteoblast activity, was analysed at diagnosis in 48 patients with multiple myeloma. At that time there was a significant relationship between disease stage (Durie-Salmon) and osteocalcin levels, lower levels being found in patients with more advanced disease. No relationship was found between osteocalcin and serum calcium levels. To date, 33 patients have died. There was a significant correlation between initial osteocalcin levels and patient survival. These findings suggest that serum osteocalcin could be a marker of prognostic significance for survival in multiple myeloma.

Adult↗
PubMed1992

Serum osteocalcin in normal and short Chinese children.

Serum osteocalcin was measured by radioimmunoassay in 200 normal children and adolescents, and seven growth hormone (GH) deficient and seven non-growth hormone deficient (NGHD) short children. There was a sex- and age-dependent change in the serum osteocalcin concentrations in normal children and adolescents with a pattern similar to the childhood height velocity curves. The serum osteocalcin concentration was in the low normal range in most patients with GH deficiency and NGHD short stature. GH therapy significantly increased the growth velocity in both groups of short children. GH treatment resulted in a significant rise in serum osteocalcin concentrations after 6 and 12 months in NGHD children but a more variable change was observed in GH-deficient children. Although osteocalcin levels may give some biochemical indication of growth, these measurements should be used together with auxological and other biochemical measurements to assess growth reliably.

Adolescent↗
PubMed1985

Plasma osteocalcin in man.

A radioimmunoassay for bovine osteocalcin has been developed. Human osteocalcin reacted identically with the bovine standard, allowing the use of this assay to measure human plasma osteocalcin. Levels were determined in 212 healthy subjects (124 men, 88 women) with an age range of 20 to 66 years. The distribution of these was skewed to the right, with the mean being 14.7 ng/ml (range 4 to 40) and the geometric mean 12.2 ng/ml. There was no alteration with age and no difference between males and females. High levels were found in chronic renal failure, Paget's disease of bone, and in primary hyperparathyroidism with severe bone disease, and there was a significant positive correlation of osteocalcin with plasma alkaline phosphatase. Low levels were found in pregnancy. Evidence is presented which suggests that the high levels measured probably reflect intact osteocalcin and not immunoreactive fragments. Our data are compared with those reported by others. Areas of disagreement are noted and discussed.

Adult↗
PubMed1989

Serum osteocalcin concentrations in patients with rheumatoid arthritis.

Osteocalcin is a non-collagenous bone matrix protein which is released into the circulation and can be measured by radioimmunoassay. Recent studies indicate that serum osteocalcin concentrations are a marker of bone formation. Because bone demineralisation is a common finding in patients with rheumatoid arthritis (RA) the serum osteocalcin concentrations and, in addition, the serum concentrations of 25-hydroxyvitamin D, parathyroid hormone, and calcitonin were measured in 29 patients with RA and in 30 control subjects. Whereas serum osteocalcin concentrations were similar in patients with RA and in control subjects, serum 25-hydroxyvitamin D concentrations were significantly decreased in patients with RA. Serum concentrations of parathyroid hormone and calcitonin in patients with RA and in control subjects were not statistically different. The normal osteocalcin concentrations in patients with RA suggest a normal rate of bone formation in these patients.

Arthritis, Rheumatoid↗
PubMed1993

Anomalous rise of serum osteocalcin following desferrioxamine treatment in aluminium intoxication.

A patient with impaired renal function, severe osteomalacia and aluminium intoxication is described. In response to Desferal (desferrioxamine) treatment, serum osteocalcin rose 8-fold whereas serum alkaline phosphatase and procollagen I peptide levels changed little. Chromatographic separation showed that the measured osteocalcin coeluted with intact osteocalcin. The osteocalcin in the serum probably comes from the liberation of pre-existing osteocalcin from the bone, concomitant with aluminium mobilisation, rather than by stimulation of de novo synthesis.

Aluminum↗
PubMed1988

Osteocalcin, parathormone and hypercalciuria.

Osteocalcin synthesis is dependent on the influence of the renal vitamin D metabolite, 1,25(OH)2D3. This metabolite is an etiological factor in some hypercalciurias, and osteocalcin may thus be a parameter for discovering them. In turn, parathormone, which stimulates 1,25(OH)2D3 synthesis, is also implicated in the hypercalciurias. Mean molecular parathormone, osteocalcin, 24-hour calciuria and the calcium/creatinine and hydroxyproline/creatinine ratios were determined in urine samples obtained after a 12-hour fast from 18 patients with absorptive hypercalciuria and 11 patients with renal hypercalciuria out of a total of 62 patients with renal lithiasis. No changes were observed in osteocalcin or parathormone, indicating that neither is valid for the diagnosis of hypercalciuria. Significant differences were only found in the Ca/Cr ratio (p less than 0.001), which was higher (0.31 +/- 0.07 vs. 0.13 +/- 0.04 mg/mg) in renal hypercalciuria than in absorptive hypercalciuria. No changes in osteocalcin have been reported in the hypercalciurias, but variations in parathormone have been reported, therefore requiring further study and thought to understand the processes involved.

Adult↗
PubMed2001

Transforming growth factor-beta1 and basic fibroblast growth factor modulate osteocalcin and osteonectin/SPARC syntheses in vitamin-D-activated pulp cells.

Vitamin D deficiency elicits hypocalcified dentin. However, little is known about the action of vitamin D on the syntheses of dentin matrix proteins. In this study, we examined the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on the expressions of osteocalcin and osteonectin/secreted protein, acidic and rich in cysteine (SPARC), by human pulp cells in the presence or absence of transforming growth factor-beta1 (TGF-beta1) or basic fibroblast growth factor (bFGF). 1,25(OH)2D3 markedly increased osteocalcin at protein and mRNA levels. The osteocalcin level induced by 1,25(OH)2D3 was decreased and increased by TGF-beta1 and bFGF, respectively. 1,25(OH)2D3 suppressed SPARC synthesis at protein and mRNA levels. TGF-beta1, but not bFGF, increased SPARC synthesis in the presence of 1,25(OH)2D3. SPARC, but not osteocalcin, increased DNA synthesis in pulp cells. These findings suggest that 1,25(OH)2D3 and growth factors interactively regulate the expression of osteocalcin and SPARC in pulp cells, and that SPARC can stimulate DNA synthesis by pulp cells.

Analysis of Variance↗
PubMed2003

Association of polymorphisms of interleukin-6, osteocalcin, and vitamin D receptor genes, alone or in combination, with bone mineral density in community-dwelling Japanese women and men.

We examined whether the -634C-->G, 298C-->T, and 2C-->T polymorphisms of the IL-6, osteocalcin, and vitamin D receptor (VDR) genes, respectively, were associated, alone or in combination, with bone mineral density (BMD) in community-dwelling Japanese women (between 1108 and 1113) or men (between 1116 and 1130) aged 40-79 yr. The -634C-->G polymorphism of the IL-6 gene and the 298C-->T polymorphism of the osteocalcin gene were associated with BMD in postmenopausal women, with the respective GG and TT genotypes representing risk factors for reduced bone mass. IL-6 and osteocalcin genotypes showed additive effects on BMD for postmenopausal women. The 2C-->T polymorphism of the VDR gene was associated with BMD in men, with the CT genotype contributing to reduced BMD. These results suggest that the IL-6 and osteocalcin genes are susceptibility loci for reduced BMD in postmenopausal women and that the VDR gene constitutes such a locus in men. The combined IL-6 and osteocalcin genotypes may prove informative for the assessment of osteoporosis in women.

Adult↗
PubMed1983

Urinary gamma-carboxyglutamic acid and serum osteocalcin as bone markers: studies in osteoporosis and Paget's disease.

Osteocalcin is a major bone matrix protein with high affinity for hydroxyapatite. This property is conferred by several residues of the calcium-binding amino acid gamma-carboxyglutamate (Gla), which requires vitamin K for its biosynthesis. Because this protein may play a role in the local control of calcium deposition or removal in mineralized tissue, we measured circulating osteocalcin levels and urinary excretion of its breakdown product, Gla, in patients with osteoporosis and Paget's disease. Studies were conducted either on a metabolic ward or in ambulatory patients. Diagnoses were established by clinical and laboratory findings, and were confirmed by histological examination in 19 of 26 patients with osteoporosis. Mean urinary Gla excretion was increased (P less than 0.001) in patients with osteoporosis by 50% above the normal mean; serum osteocalcin, however, was not significantly different from normal. In Paget's disease patients, this pattern was reversed; serum osteocalcin levels were increased 3-fold (P less than 0.001), while urinary Gla excretion was consistently normal, regardless of the extent or activity of the disease. These data demonstrate that measurements of urinary Gla and serum osteocalcin may provide important insights into the metabolic derangements in these and other bone disorders.

1-Carboxyglutamic Acid↗