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PubMed1989

Histochemical detection of osteocalcin in normal and pathological human bone.

We investigated the immunohistochemical localization of osteocalcin in demineralized, paraffin-embedded normal and pathological human bone. Acid decalcification protocols appeared to be more suitable for osteocalcin detection than mild chelating agents. In normal lamellar bone, osteocalcin was detected in osteocytes and along the lamellar bone matrix in fine granular deposits. Under pathological conditions (osteomyelitis, neoplasia), appositional bone showed immunoreactivity in osteoblasts and osteocytes but not in the provisory woven bone matrix. Intense immunoreactivity could be seen at the cell borders of osteoclasts and the bone margins of Howship lacunae. In primary bone-forming tumors, osteocalcin immunoreactivity was detected in osteoblasts and their malignant counterparts. On the basis of these results, we conclude that optimal preservation of osteocalcin is obtained through mild acid decalcifiers. Osteocalcin is deposited in bone matrix, especially that of metabolically inactive bone. In neoplasms, osteocalcin could be a marker of osteoblastic differentiation.

Bone Neoplasms↗
PubMed1984

Clinical evaluation of bone turnover by serum osteocalcin measurements in a hospital setting.

Serum levels of osteocalcin, the major noncollagenous bone protein, are elevated in patients with certain metabolic bone diseases, but the effects of other illnesses on serum osteocalcin levels are not known. We measured serum osteocalcin concentrations in 250 patients in a rehabilitation hospital who suffered from various illnesses. Mean serum osteocalcin levels were elevated in patients with 1) recent hip fracture who required open reduction and pin insertion (mean +/- SE, 19.0 +/- 3.2 ng/ml), 2) primary (22.0 +/- 4.9 ng/ml) or secondary hyperparathyroidism (51.6 +/- 9.9 ng/ml), 3) Paget's disease of bone (22.7 +/- 6.1 ng/ml), or 4) metastatic skeletal disease who had not received therapy (37.5 +/- 11.3). Mean serum osteocalcin levels were normal in patients who had received 1) a hip prosthesis for a recent fracture or for severe degenerative joint disease of the hip (6.4 +/- 0.9 ng/ml), 2) recent chemotherapy or irradiation for bone metastases (6.1 +/- 1.3 ng/ml), or 3) a variety of medical problems not related to bone disease (5.2 +/- 0.3 ng/ml). Serum osteocalcin and alkaline phosphatase values did not correlate. This study demonstrates that serum osteocalcin levels are normal in disorders not involving bone, can be used in a general-hospital setting, where concomitant illnesses are present, and may provide additional information for the clinical evaluation of metabolic bone disease.

Adult↗
PubMed1985

Osteocalcin in human serum: a circadian rhythm.

Osteocalcin, the vitamin K-dependent protein synthesized in bone, is found in blood. The level of circulating osteocalcin has recently been used as an indicator of the rate of bone turnover. We measured serum osteocalcin during 24-h periods in 6 normal 20- to 30-yr-old men and 4 women. Blood was sampled via an indwelling venous catheter every 30 or 60 min for 24 h. Circadian rhythmicity in circulating osteocalcin was found in 9 of the 10 individuals studied. Osteocalcin levels fell during the morning, rose in the afternoon and early evening, and reached a peak nocturnally. There were no consistent correlations between osteocalcin concentrations and circulating levels of ionized calcium, total calcium, or inorganic phosphate in the subjects tested. This study illustrates the importance of regulating the time of blood sampling for osteocalcin determinations in clinical investigations of metabolic bone disease.

Adult↗
PubMed2001

IGF-I, osteocalcin, and bone change in pregnant normotensive and pre-eclamptic women.

Pre-eclampsia is a pregnancy disorder of uncertain etiology that affects 5-10% of all pregnancies, with symptoms typically presenting around or after 20 wk gestation. We hypothesized that IGF-I, osteocalcin, and bone loss would be different among women with pre-eclampsia compared with normotensive pregnant women. There were 962 pregnant healthy women, aged 12-35, who were assessed at entry to care, at 28 wk, and at delivery for osteocalcin and IGF-I concentrations. Bone ultrasound was measured at entry to care and at 6 wk postpartum, whereas bone mineral density was measured by dual x-ray densitometry at delivery. There were 64 women (6.7%) among the women being followed who developed pre-eclampsia. In women with pre-eclampsia, IGF-I concentrations were 74% greater in the third trimester compared with the first trimester, whereas there was little change in osteocalcin concentrations. In contrast, normotensive women had an average increase of 43% in IGF-I concentrations accompanied by a 63% decline in osteocalcin concentrations. In women with pre-eclampsia, IGF-I and osteocalcin concentrations were significantly correlated (r = 0.48 and 0.43) at both the first and third trimester time points, but only in the third trimester among normotensive women (r = 0.27). The bone change difference between the two groups was not statistically significant. Women with pre-eclampsia appear to have an exaggerated IGF-I responsiveness compared with women who are normotensive; however, the strong correlation between IGF-I and osteocalcin in women with pre-eclampsia suggests that the IGF-I is able to retain its role as a local regulator of bone remodeling, as indicated by the osteocalcin concentrations.

Adult↗
PubMed1997

Ascorbic acid-dependent activation of the osteocalcin promoter in MC3T3-E1 preosteoblasts: requirement for collagen matrix synthesis and the presence of an intact OSE2 sequence.

Osteocalcin is a hormonally regulated calcium-binding protein made almost exclusively by osteoblasts. In normal cells, osteocalcin expression requires ascorbic acid (AA), an essential cofactor for osteoblast differentiation both in vivo and in vitro. To determine the mechanism of this regulation, subclones of MC3T3-E1 preosteoblasts were transiently transfected with 1.3 kb of the mouse osteocalcin gene 2 promoter driving expression of firefly luciferase. AA stimulated luciferase activity 20-fold after 4-5 days. This response was stereospecific to L-ascorbic acid and was only detected in MC3T3-E1 subclones showing strong AA induction of the endogenous osteocalcin gene. Similar results were also obtained in MC3T3-E1 cells stably transfected with the osteocalcin promoter. A specific inhibitor of collagen synthesis, 3,4-dehydroproline, blocked AA-dependent induction of promoter activity, indicating that regulation of the osteocalcin gene requires collagen matrix synthesis. Deletion analysis of the mOG2 promoter identified an essential region for AA responsiveness between -147 and -116 bp. This region contains a single copy of the previously described osteoblast-specific element, OSE2. Deletion and mutation of OSE2 in DNA transfection assays established the requirement for this element in the AA response. Furthermore, DNA-binding assays revealed that MC3T3-E1 cells contain OSF2, the nuclear factor binding to OSE2, and that binding of OSF2 to OSE2 is up-regulated by AA treatment. Taken collectively, our results indicate that an intact OSE2 sequence is required for the induction of osteocalcin expression by AA.

Animals↗
PubMed1997

Plasmin-mediated proteolysis of osteocalcin.

Plasmin cleaves osteocalcin at a site within its carboxyl end, thus creating an N-midterminal 1-43 and a short C-terminal 44-49 peptides. The products of the cleavage were identified by matrix assisted laser desorption ionization time of flight mass spectrophotometry and by reversed phase high performance liquid chromatography followed by N-terminal sequence determination. When separated by sodium dodecyl sulfide-polyacrylamide gel electrophoresis in the presence of reducing agents, large (LF; N-midterminal) and a small molecular weight (SF; C-terminal) fragments can be identified. The major cleavage site involves arg43-arg44 amino acid residues, and the resulting 44-49 C-terminal fragment appears as a slow migrating band on native gels (SFnat). Elevated levels of calcium ion inhibit the plasmin-mediated lysis of osteocalcin. Plasmin-mediated cleavage of osteocalcin occurs both in solution and when bound to hydroxyapatite. Both osteocalcin cleavage products detach from the hydroxyapatite substrate. Diisopropyl fluorophosphate-inhibited plasmin does not displace osteocalcin from the hydroxyapatite surface. Previously, the C-terminal pentapeptide has been shown to be chemotactic for bone cells while bone particles lacking osteocalcin were resistant to bone resorption. We therefore hypothesize that the plasmin-mediated digestion of free and hydroxyapatite-bound osteocalcin could play a role in the regulation of bone remodeling.

Amino Acid Sequence↗
PubMed1989

Osteocalcin: characterization and regulated expression of the rat gene.

An osteocalcin gene was isolated from a rat genomic DNA library, and sequence analysis indicated that the mRNA is represented in 953 nucleotide segment of DNA consisting of 4 exons and 3 introns. Although the introns in the rat gene are larger, its overall organization is similar to the human gene. Analysis of the 5' flanking sequences of the rat gene shows a modular organization of the promotor as reflected by the the presence of at least 3 classes of regulatory elements. These include (1) typical sequences associated with most genes transcribed by RNA polymerase II (e.g. TATA, CAAT, AP1, AP2), (2) a series of consensus sequences for cyclic nucleotide responsive elements and several hormone receptor binding-sites (estrogen, thyroid and clusters of AG-rich putative Vitamin D responsive elements); and (3) a 24 nucleotide highly conserved sequence between the rat and human gene having a CAAT motif as a central element, designated as an "osteocalcin box." Two regulatory factors of osteocalcin gene expression have been identified. First, contained within the 600 nucleotides immediately upstream from the transcription initiation site are sequences which support Vitamin D dependent transcription of the rat osteocalcin gene. 1,25(OH)2D3 increases osteocalcin mRNA by 6-20 fold increases. In contrast, up to a 200 fold increase in osteocalcin gene expression occurs with mineralization of the extracellular matrix produced by osteoblasts. We propose osteocalcin is a bone-specific marker protein of the mature osteoblast in a mineralizing matrix.

Animals↗
PubMed2000

Serum osteocalcin and urinary crosslaps are suitable markers of bone turnover in response to short-term hormone replacement therapy.

In this study we evaluated the effect of short-term hormone replacement therapy (HRT) on bone formation (serum osteocalcin) and resorption markers (urinary type I collagen peptides (crosslaps), urinary total free pyridinoline (TPYRI) and urinary free deoxypyridinoline (DPYRI)) as well as female sex hormones (serum estradiol, follicle stimulating hormone (FSH) and luteinizing hormone (LH)) in a group of early postmenopausal women with severe estrogen deficiency. The 46 healthy postmenopausal women with serum estradiol levels < 10 ng/l were subsequently divided into two groups, according to their compliance with HRT. In the group taking HRT significant changes from baseline values could be observed in estradiol, FSH, urinary crosslaps and serum osteocalcin levels after 6 months, whereas no changes could be observed in LH, TPYRI and DPYRI from baseline values. In the group which refused HRT all values were increased relative to baseline values, indicating increased bone turnover. Serum osteocalcin and urinary crosslaps were significantly decreased in women taking HRT in comparison to the group refusing HRT. After 6 months the treated patients showed a decrease in urinary crosslaps of 42% (SD 12%) and in serum osteocalcin of 24% (SD 6%) in comparison with baseline values. In patients who refused HRT, urinary crosslaps were increased by 43% (SD 20%) and serum osteocalcin levels decreased by 2% (SD 9%) compared to baseline values. In postmenopausal women suffering from severe estrogen deficiency (estradiol < 10 ng/l) serum osteocalcin and urinary crosslaps are significantly increased, indicating a clear correlation between estrogen deficiency and an increase in bone resorption as well as bone formation. The recommended HRT dose was sufficient to reduce the rate of bone turnover to premenopausal values. Serum osteocalcin and urinary crosslaps are suitable candidates not only for the assessment of a high postmenopausal bone turnover, but also for monitoring the response to and for verifying the actual intake of HRT or other antiresorptive treatment.

Administration, Oral↗
PubMed1999

Osteocalcin binds tightly to the gamma-glutamylcarboxylase at a site distinct from that of the other known vitamin K-dependent proteins.

Vitamin K-dependent proteins contain a propeptide that is required for recognition by the enzyme gamma-glutamylcarboxylase. Substrates used in vitro for carboxylation studies lacking a prosequence are characterized by Km values in the millimolar range, whereas the Km for peptides containing a prosequence is three or four orders of magnitude smaller. Here we report that descarboxy-osteocalcin is an exception in this respect. With descarboxy-osteocalcin in purified propeptide-free recombinant carboxylase, the Km was 1.8 microM. Furthermore, osteocalcin was an inhibitor of descarboxy-osteocalcin carboxylation with a Ki of 76 microM. In contrast with the other vitamin K-dependent proteins, free propeptides do not inhibit descarboxy-osteocalcin carboxylation. Moreover, propeptide-containing substrates were inhibited neither by osteocalcin nor by its propeptide. From our studies we conclude that descarboxy-osteocalcin must have an internal recognition sequence that binds to gamma-glutamylcarboxylase at a site different from the propeptide-recognition site.

Amino Acid Sequence↗
PubMed1999

[Reference values for IGF-I, IGFBP-1, IGFBP-3 and osteocalcin in healthy children in Zaragoza].

OBJECTIVE: Our aim was to estimate reference values for basal serum concentrations of insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-1, IGFBP-3 and osteocalcin in healthy children of Zaragoza. PATIENTS AND METHODS: The reference population consisted of healthy children between 0 and 14 years of age with normal weight and height and living in the metropolitan area of Zaragoza (Spain). It was a transversal study. Immunoradiometric assays were used to determine basal serum IGF-I, IGFBP-1, IGFBP-3 and osteocalcin concentrations. Reference values and ranges were estimated according to the recommendations of the International Federation of Clinical Chemistry. RESULTS: Reference values have been classified according to age, sex and pubertal stage. IGF-I, IGFBP-1, IGFBP-3 and osteocalcin concentrations differ during the pubertal period according to age. There are differences in IGF-I, IGFBP-3 and osteocalcin levels between prepuberty and puberty and differences in IGF-I and osteocalcin levels among the pubertal stages. Sex did not influence IGF-I or IGFBP-1 concentrations and there were punctual differences in IGFBP-3 and osteocalcin levels between girls and boys. CONCLUSIONS: Sincere there are differences in IGF-I, IGFBP-1, IGFBP-3 and osteocalcin reference values according to age, sex, pubertal stage and immunoassays, it is necessary to establish the reference values for each population and laboratory in accordance with these parameters.

Adolescent↗
PubMed2006

[Bone and bone related biochemical examinations. Bone and collagen related metabolites. Osteocalcin (OC)].

Osteocalcin is produced by mature osteoblasts and primarily deposited in the extracellular matrix of skeletal tissue. It has been shown that serum osteocalcin is a marker of osteoblastic activity, and the levels reflect the rate of bone formation. The first osteocalcin assays were competitive radioimmunoassays using bovine osteocalcin as a standard, and a new generation of assays was developed to measure the major circulating forms of the protein, which is the intact and the large N-terminal fragment. Since osteocalcin binds to hydroxyapatite crystal after gamma-carboxylation at three residues, increased amounts of immature undercarboxylated osteocalcin might reflect risks for fractures. However, at present, measurement of osteocalcin does not substitute for bone mass measurement and only provide limited clinical values on evaluation of patients with osteoporosis or metabolic bone diseases.

Biomarkers↗
PubMed1991

Circadian rhythms of osteocalcin in equine serum. Correlation with alkaline phosphatase, calcium, phosphate and total protein levels.

The purpose of the study was to determine whether there were circadian variations in serum osteocalcin in normal horses and to determine whether it was important to regulate the time of blood sampling in clinical investigations. Osteocalcin or bone Gla-protein (BGP), alkaline phosphatase, total calcium, phosphate and total protein were studied over a 24 h period. Blood samples were taken every 60 min from nine adult Standardbred horses. There was a correlation between serum levels of alkaline phosphatase (r = 0.3, p less than 0.01), phosphate (r = 0.42, p less than 0.01) and serum osteocalcin levels. There was a very marked individual effect on serum levels of osteocalcin and alkaline phosphatase (p less than 0.01). This effect was present for phosphate levels but not significant for total calcium. The individual effect was lower and time effect was higher for serum osteocalcin if the subjects were divided into two age groups, one of horses of five years or less (n = 4) and a second group older than five years (n = 5). In both groups a circadian rhythmicity was observed. Serum osteocalcin showed a biphasic pattern. Levels were constant during daytime (light period) and underwent significant variations during the night (dark period), going through a nadir at 2000 h and through a maximum peak at 0500 h. It was concluded that in normal horses the blood osteocalcin level follows a circadian variation. Also daytime (light period) seems to be the more appropriate period for blood sampling.

Alkaline Phosphatase↗
PubMed1991

Osteocalcin concentrations in plasma prepared with different anticoagulants.

We investigated the effects on plasma osteocalcin concentrations of different anticoagulants used to collect the blood samples. Plasma osteocalcin concentrations measured by enzyme immunoassay and radioimmunoassay are influenced by the nature of the anticoagulants used. The most significant difference between concentrations found in plasma and serum was seen with oxalate/fluoride anticoagulant, which reduced osteocalcin concentrations to 37.3% of serum values. This is probably related to increased hemolysis with this anticoagulant compared with osteocalcin concentrations in plasma prepared with other anticoagulants. Samples prepared with sodium citrate (0.105 mol/L) or lithium heparin gave values 92.4% and 83.6% of those obtained with matched serum samples. Osteocalcin concentrations were relatively stable in plasma and serum at -20 degrees C for two freeze/thaw cycles. In blood from 100 patients there was a good correlation between osteocalcin concentrations in serum and plasma (lithium heparin) (r2 = 0.831); the slope and intercept (+/- SE) were 0.924 +/- 0.04 and 4.92 +/- 1.25 micrograms/L, respectively. However, in 10 patients, serum osteocalcin concentrations were two- to threefold higher than those in matched plasma samples.

Adult↗
PubMed1989

[Clinical evaluation of osteocalcin in chronic hemodialysis patients].

Serum level of osteocalcin was measured by radioimmunoassay in 52 patients with chronic renal failure and 92 control subjects. The patients were treated by usual hemodialysis over a 3-month period. The osteocalcin level of the patients was significantly higher than that of the control subjects, but the patients with diabetic nephropathy had a lower osteocalcin level than the patients with non-diabetic nephropathy. There was a significant correlation between serum osteocalcin level and alkaline phosphatase or PTH level. On the other hand, there was no relationship between serum osteocalcin level and various parameters such as bone mineral contents, and bone cortex volume measured by the microdensitometry method. Hemodialysis affected the serum osteocalcin level. The clinical value of osteocalcin as a parameter of bone formation in chronic hemodialysis patients was discussed.

Adult↗
PubMed1989

Serum osteocalcin and bone mineral metabolism following successful renal transplantation.

Serum osteocalcin (bone gla protein, BGP), a vitamin K-dependent non-collagenous bone protein and its relationship to other markers of bone and mineral metabolism were studied cross-sectionally in varying numbers of patients before and over 240 days following renal transplantation. Marked elevation of serum creatinine (11.9 +/- 0.76 mg/dl), osteocalcin (216.9 +/- 7 ng/ml), parathyroid hormone (PTH, mid-molecule fragment) (24.5 +/- 3.6 ng/ml), alkaline phosphatase (255.2 +/- 54.7 IU/l) and phosphorus (5.6 +/- 0.3 mg/dl) were noted preoperatively. Serum calcium levels remained normal throughout the study period while phosphate levels normalized within one week after transplantation. PTH levels progressively decreased postoperatively over the study period but were still elevated well above normal. Serum osteocalcin decreased to near normal values at 60-90 days after surgery. Both PTH and alkaline phosphatase correlated significantly with osteocalcin preoperatively and postoperatively. The relatively depressed values of osteocalcin in the face of still elevated PTH levels post-transplantation was attributed to the effect of immunosuppressive corticosteroid therapy. The significant correlation between PTH and osteocalcin suggests that osteocalcin may be as or more sensitive a measurement of bone turnover than alkaline phosphatase pre- and post-transplantation.

Adolescent↗
PubMed1986

[Osteocalcin (or bone gla-protein), a new biological marker for studying bone pathology].

Osteocalcin, also called bone gla-protein, is a bone matrix protein synthetized specifically by osteoblasts. It circulates in blood where it can be assayed by the radioimmune method. We measured osteocalcin serum levels in 169 adult controls and 161 patients with different disseminated or localized bone diseases. The normal concentration of 6.2 +/- 0.2 ng/ml increases significantly with age. Serum osteocalcin levels are considerably increased in renal osteodystrophy (114 +/- 23 ng/ml) and to a lesser degree in primary hyperparathyroidism (15.9 +/- 2.8 ng/ml) and Paget's disease (11.4 +/- 0.9 ng/ml), all diseases characterized by increased bone turnover. High levels are also encountered in osteomalacia (9.7 +/- 0.9 ng/ml). Conversely, serum osteocalcin levels are significantly decreased in patients under long-term corticosteroid therapy (4.3 +/- 0.5 ng/ml); they remain normal in patients with bone myeloma and bone metastases under treatment. Finally, osteocalcin is normal in patients with osteoporosis, but its level reflects that of bone turnover as evaluated by iliac bone biopsy. The circulating osteocalcin therefore is the first specific and sensitive marker for bone turnover. Serum osteocalcin measurements make it possible to evaluate the osteoblastic bone formation without biopsy and should provide information on the effectiveness of drugs acting on the bone-forming process.

Adrenal Cortex Hormones↗
PubMed1988

Fracture healing and osteocalcin metabolism in vitamin K deficiency.

Osteocalcin (a vitamin K-dependent, bone-specific protein) is widely accepted as a marker of osteoblastic activity. The present study was conducted to determine if a vitamin K deficiency would affect fracture healing by virtue of an alteration in osteocalcin metabolism. Thirty male Sprague-Dawley rats were divided into two groups. The control group was fed a diet that was lacking in, but offered water replete with vitamin K. The experimental group was fed a vitamin K-deficient diet and was offered water that was lacking in vitamin K. After two weeks, vitamin K deficiency was established in the experimental group as shown by decreased urinary excretion of gamma-carboxyglutamic acid and an elevation of serum prothrombin times to between two to two and one-half times the control values. At this time, a standard, closed femoral fracture was produced. Six weeks later, the animals were killed. The bones were biomechanically tested in torsion. Subsequent to mechanical testing, the calluses were retrieved, and the osteocalcin content and the degree of gamma carboxylation of the osteocalcin in the calluses were measured. The results show that despite significant alterations in the gamma carboxylation of osteocalcin and elevation of prothrombin times to two to two and one-half times the control values, there were no differences in the mechanical properties of the calluses. Furthermore, there were no differences in the content or gamma carboxylation of osteocalcin in these calluses. Apparently, in vitamin K deficiency, fracture callus achieves normal mechanical properties and may have a mechanism for the gamma carboxylation of glutamic acids in osteocalcin despite a substantial depression of this activity in the rest of the body.

1-Carboxyglutamic Acid↗
PubMed1993

[The concentration of osteocalcin in the culture media of bone cultured in vitro subjected to intermittent mechanical load with the addition of 1,25(OH)2D3].

The osteocalcin concentration decreases in the medium of bones submitted to intermittent mechanical forces in organotypic culture (6). The functional significance of this behaviour is unknown. To investigate the dynamics of the osteocalcin production, we added 1,25(OH)2D3 to the culture medium to stimulate osteoblastic production of the osteocalcin. The bones were isolated from 12 day-old rats, placed in culture medium added with 10(-8) M 1,25(OH)2D3 and subjected 1/2 h daily to an intermittent mechanical load (11.6 Kg/mm2) at 1 Hz frequency. 12, 24 and 48 hours after the loading the alcaline phosphatase activity (p-nitrophenol as substrate) and the osteocalcin concentration (RIA method) were evaluated in the media. The phosphatase activity does not change in the control bones, while it significantly increases in the loaded bones 24 h after loading (fig. 1). The osteocalcin concentration increases significantly in the control bones, with a peak at 24 h; in the loaded ones, it does not increase at 24 h with respect to 12 h, while it increases 48 h after loading, but at a lower level than the control bones. Since the increase of the alcaline phosphatase activity is a sign of new bone production, our results indicate that an osteoid deposition is likely to take place in the loaded bones, not in the control ones. The increase in the control bones of osteocalcin concentration is in agreement with the results of other researches (7), and indicates that the osteoblasts of this experimental system are able to produce osteocalcin under appropriate conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗