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PubMed1991

Impairment of gamma carboxylation of circulating osteocalcin (bone gla protein) in elderly women.

Osteocalcin, also called bone gla protein, is a unique noncollagenous protein of the extracellular matrix of bone that circulates in blood. Oseteocalcin contains three residues of the vitamin K-dependent gamma-carboxyglutamic acid (gla) responsible for the affinity of osteocalcin for bone mineral. In animals treated with the vitamin K antagonist warfarin, the osteocalcin content of bone is markedly reduced and the fraction of osteocalcin released into the circulation is increased. Most studies have shown that osteocalcin increases with aging in women, reflecting an increase in bone turnover, especially after the menopause. To determine if this increase in osteocalcin could be associated with impaired carboxylation, we measured total and noncarboxylated osteocalcin in the serum of 72 women of various ages: 22 premenopausal (31 +/- 7 years old), 20 early postmenopausal (54 +/- 3 years), and 30 elderly women (85 +/- 8 years). As previously reported, total serum osteocalcin was significantly increased in early postmenopausal and elderly women. Noncarboxylated serum osteocalcin was slightly increased in early postmenopausal women (0.95 +/- 0.4 versus 0.65 +/- 0.5 ng/ml in premenopausal women), markedly elevated in elderly women (1.59 +/- 1.1 ng/ml, p less than 0.001), and correlated with age (r = 0.47, p less than 0.001). Elderly women had values of the same magnitude as in 10 patients on chronic warfarin therapy (1.94 +/- 1.1 ng/ml). As a consequence, the increase in carboxylated serum osteocalcin was significant in early postmenopausal women but not in elderly women. Serum levels of vitamin K1 and of menaquinones 6, 7, and 8 were measured in some of the young and elderly women.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

Measurement of serum osteocalcin with a human-specific two-site immunoradiometric assay.

We developed a sensitive and specific two-site radioimmunoassay (IRMA) for human osteocalcin using human osteocalcin as a standard and two monoclonal antibodies raised against human osteocalcin purified from human cortical bone, a solid-phase anti-25-37 region and a tracer anti-5-13 sequence of the molecule. A wide range of osteocalcin levels (up to 300 ng/ml) can be measured with a sensitivity of 0.4 ng/ml. The intra- and interassay coefficients of variation are less than 4 and 6%, respectively. The recovery of human osteocalcin from serum samples ranges from 96 to 103%. IRMA was linear for serial sample dilutions in a wide range of serum osteocalcin levels, even in patients with chronic renal failure on hemodialysis. Depletion of serum in intact osteocalcin demonstrated that IRMA detects, in addition to the intact peptide, a large N-terminal midregion fragment that represents about 50% of total osteocalcin levels in normals and patients with Paget's disease and up to 75% in patients with chronic renal failure. This large fragment, previously unrecognized because it cannot be distinguished from intact osteocalcin with gel filtration chromatography, is not generated in vitro by incubation of the serum up to 26 h. We measured osteocalcin in the serum of 309 healthy adults (180 men and 129 women, age range 20-95 years), 36 patients with Paget's disease, 12 patients with primary hyperparathyroidism, 70 patients with chronic renal failure on hemodialysis, and 10 patients on corticosteroid therapy, simultaneously with human IRMA and with a conventional radioimmunoassay (RIA) based on bovine reagents. A tight correlation (r = 0.889) was observed between the two assays in the normal population, but the values obtained with IRMA were about threefold higher (mean 23.3 +/- 10.5 versus 7.5 +/- 3.4 ng/ml) than those obtained with RIA. Reported as Z scores, that is, number of standard deviations from the predicted normal mean adjusted for sex and age, these two assays (IRMA and RIA) gave concordant results in patients with Paget's disease (4.05 +/- 6.21 versus 2.41 +/- 2.53), primary hyperparathyroidism (4.14 +/- 7.17 versus 2.13 +/- 2.28), chronic renal failure (25.32 +/- 24.49 versus 6.93 +/- 5.48), and glucocorticoid treatment (-1.48 +/- 0.78 versus -1.11 +/- 0.57). However, IRMA was more discriminant from controls for all these metabolic bone diseases because the absolute values of mean Z scores with IRMA were significantly higher than those obtained with the RIA (p < 0.05-0.0001).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1994

Characterization of immunoreactive forms of human osteocalcin generated in vivo and in vitro.

Three monoclonal antibodies recognizing the 5-13, 25-37, and 43-49 sequence of the human osteocalcin were used in competitive and two-site radioimmunoassays (RIA) to characterize specifically various immunoreactive forms of circulating human osteocalcin. The intact molecule accounts for 36% of total in normals (2.6 nM), 46% in patients with osteoporosis (3.1 nM), and 26% in chronic renal failure (6.9 nM). Four fragment were detected in addition to the intact molecule in the serum of healthy adults and patients with metabolic bone disease. N-terminal, mid, and mid C-terminal fragments were present in minute amounts (each accounting for 5-14% of the total circulating osteocalcin immunoreactivity). In contrast, the N-terminal midfragment, probably resulting from the cleavage around amino acids 43-44, represents about 30% (2 nM) of the total osteocalcin immunoreactive level in normals and patients with osteoporosis and up to 50% (13 nM) in patients with chronic renal failure. This large N-terminal midfragment, representing 75-80% of the intact osteocalcin level, is not lower when the plasma assay is performed immediately after sampling (within 20 minutes at 4 degrees C with proteinase inhibitors), indicating that it circulates in vivo. In addition, this fragment was detected in the supernatant of osteoblastic cells, representing about 28% of the intact peptide. Levels of N-terminal midfragment were not changed after treatment of patients with metabolic bone disease (Paget's disease, reflex sympathetic dystrophy, fibrous dysplasia, and osteoporosis) by bisphosphonate, suggesting that it is not released during bone resorption. The osteocalcin level measured with the two-site immunoradiometric assay specific for the intact molecule or with a conventional bovine RIA was rapidly decreased after incubation of serum at room temperature (-20 and -15%, respectively, after 3 h), whereas the total level of intact osteocalcin plus N-terminal midfragment was not changed. Intact osteocalcin loss can be partially avoided by proteinase inhibitors and by incubating serum at 4 degrees C. In conclusion, we characterized multiple immunoreactive forms of osteocalcin that circulate in addition to the intact molecule, none of them being specifically altered in osteoporosis. The N-terminal midfragment circulates in a large amount, probably resulting from cleavage of the intact molecule in the circulation and/or at peripheral sites. These fragments can also be generated in vitro by proteolytic degradation of the intact molecule. To obtain reliable intact osteocalcin values but also reliable levels measured with conventional competitive RIA, careful control of the sampling conditions is warranted.

Adult↗

PubMed1994

Effects of transforming growth factor beta 1 on the regulation of osteocalcin synthesis in human MG-63 osteosarcoma cells.

Treatment of human MG-63 osteosarcoma cells with human recombinant transforming growth factor beta 1 (TGF-beta 1) was found to inhibit cell proliferation. In addition, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]-induced osteocalcin synthesis was greatly influenced by TGF-beta 1. Dose- and time-dependent inhibition was seen both in medium osteocalcin and the corresponding mRNA concentrations. Furthermore, TGF-beta 1 decreased osteocalcin synthesis modulated negatively by dexamethasone or positively by retinoic acid. The stability of osteocalcin mRNA was not decreased by the TGF-beta 1 treatment, but in vitro transcription assays demonstrated diminished osteocalcin gene transcription caused by the TGF-beta 1 treatment. Binding of vitamin D receptor (VDR) to an oligonucleotide probe containing the osteocalcin vitamin D response element (VDRE) was not influenced by TGF-beta 1, however. Incubation of the cells with the serine/threonine kinase inhibitor H-7 did not block the ability of TGF-beta 1 to decrease osteocalcin synthesis but caused a further inhibition. Also, the 1,25(OH)2D3-induced osteocalcin synthesis was decreased by H-7 treatment, suggesting that phosphorylation as such is involved in the transcriptional activation mechanism of VDR. These results demonstrate that TGF-beta 1 is a strong inhibitor of the synthesis of osteocalcin, a calcium binding protein participating in bone mineralization, by counteracting the stimulatory effects of other hormones on its synthesis. We further suggest that TGF-beta 1 affects the synthesis of osteocalcin at the level of transcription through mechanism(s) different from the serine/threonine kinase pathway.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1996

Posttranscriptional regulation of osteocalcin mRNA in clonal osteoblast cells by 1,25-dihydroxyvitamin D3.

A well-established action of 1,25(OH)2D3 in bone is stimulation of osteocalcin synthesis. Here we show that osteocalcin mRNA regulation by 1,25(OH)2D3 in clonal osteoblast cells (ROS 17/2.8), besides occurring at a transcriptional level, is also regulated by a posttranscriptional mechanism. Transcriptional "run-on" assays performed after 1, 3, 4, and 24 h of treatment with 1,25(OH)2D3 (50 nM) indicate an approximate twofold increase in the rate of osteocalcin transcription at each time point examined. Actinomycin D (AD) was used as a transcriptional inhibitor to measure the osteocalcin message half-life in ROS 17/2.8 cells. A 24-h treatment of ROS 17/2.8 cells with 1,25(OH)2D3 resulted in prolongation of osteocalcin half-life from 7.0 +/- 1.0 h in untreated cells to 28.0 +/- 0.7 h in the treated cells. Inhibition of protein synthesis by cycloheximide resulted in moderate stabilization of osteocalcin mRNA (t1/2 = 7.7 h in the absence and 14.0 h in the presence of cycloheximide) in ROS 17/2.8 cells. However, osteocalcin mRNA half-life in cells that had been treated with 1,25(OH)2D3 was not further prolonged in the presence of cycloheximide (t1/2 = 22.1 h in the absence and 22.6 h in the presence of cycloheximide). The osteocalcin poly(A) tail length was not altered by 1,25(OH)2D3 treatment and, therefore, may not play a role in 1,25(OH)2D3-induced mRNA stabilization. Osteocalcin mRNA expressed by a cytomegalovirus (CMV) promoter in transfected U937 cells was shown to be stabilized by 1,25(OH)2D3 (control cells, t1/2 = 5.0 +/- 0.6 h; treated cells, t1/2 = 22.0 +/- 0.2 h). This suggests that cellular events resulting in mRNA stabilization can operate independently from events that mediate transcriptional regulation of osteocalcin by 1,25(OH)2D3.

Animals↗

PubMed1991

Serum osteocalcin levels in primary hyperparathyroidism.

The serum levels of osteocalcin, a 49-amino-acid bone-matrix protein, have been found to be a specific biochemical parameter of bone formation. The aim of our study was to compare the sensitivity of serum osteocalcin levels with that of alkaline phosphatase in the evaluation of patients with primary hyperparathyroidism. In 40 patients with biochemically and histologically confirmed primary hyperparathyroidism, the serum levels of osteocalcin, intact parathyroid hormone, alkaline phosphatase, calcium, phosphorus, and creatinine were determined preoperatively. The serum levels of osteocalcin were elevated in 22 patients (55%), whereas the serum levels of alkaline phosphatase were increased in 18 patients (45%). In 10 patients (25%) the serum levels of osteocalcin, but not those of alkaline phosphatase, were increased, whereas in six patients the activity of alkaline phosphatase was high, but the serum osteocalcin levels were normal. When the biochemical data of the patients with increased serum osteocalcin levels were compared with those of the patients with serum osteocalcin levels within the normal range, the serum levels of intact parathyroid hormone and alkaline phosphatase were significantly increased in the group of patients with elevated serum osteocalcin levels. Our data indicate that serum osteocalcin levels might be a clinically useful additional parameter in the evaluation of patients with primary hyperparathyroidism.

Adult↗

PubMed1990

Sex- and age-related changes in bone and serum osteocalcin.

We measured bone osteocalcin concentrations in EDTA extracts from iliac crest cortical bone specimens obtained postmortem from 63 men and 71 women (age range 19-90 years), and serum osteocalcin levels in healthy blood donors, 49 men and 49 women (age range 21-65 years). Bone and serum osteocalcin concentrations were higher in men than in women, and an age-related decline was observed in both sexes. In women, however, a temporary increase in serum (P less than 0.05) osteocalcin was seen in the sixth decade. This study shows sex- and age-related changes in bone osteocalcin consistent with changes in serum osteocalcin, confirming that serum measurement of osteocalcin reflects bone levels. As osteocalcin reflects osteoblastic activity and thus bone formation, the overall decline in bone and serum osteocalcin in men and women, and the increase in serum osteocalcin in the sixth decade in women, indicate that aging is associated with a decrease in bone formation and turnover and that osteoblastic activity and bone turnover are stimulated at the menopause.

Adult↗

PubMed2000

Development and application of a synthetic peptide-based osteocalcin assay for the measurement of bone formation in mouse serum.

The mouse is frequently used as an animal model to study skeletal mechanisms relevant to humans. Biochemical markers of bone formation and resorption provide one of the key parameters for assessing skeletal metabolism. One biochemical marker that has proven to be useful in the studies of mouse skeletal metabolism is osteocalcin. Assay for osteocalcin is available in the mouse. The present study describes development of an osteocalcin radioimmunoassay (RIA) using a synthetic peptide. Intact osteocalcin purified from mouse bone extracts shows parallel displacement with synthetic peptide. Sensitivity of the RIA was 19 ng/ml. The average (n = 9) intra- and interassay coefficient of variation for two controls was less than 10%; the averaged recoveries were 106%. The osteocalcin concentration measured by peptide RIA shows a high correlation (r = 0.88, n = 117, P < 0.0001) with an intact osteocalcin assay. In addition, when the intact assay and peptide assays were applied to evaluate skeletal perturbation, similar results were obtained. Accordingly, osteocalcin levels measured by both intact and peptide-based RIA in 8-week C57BL/6J (n = 8) mice treated with PTH 1-34 were twofold higher compared with the vehicle-treated control group. Further studies of the application of the peptide-based RIA for osteocalcin revealed that osteocalcin levels in 4-week postovariectomized (OVX) C57BL/6N mice (n = 10) were 80% higher than the sham-operated (n = 10) mice receiving vehicle. OVX mice receiving weekly injections of estradiol (400 microg/kg body weight) were 38% lower compared with the OVX group treated with vehicle. In conclusion, the peptide-based RIA has analytical and a discriminative power similar to that of the intact osteocalcin assay but has the advantage that the resources for this assay are much easier to accrue.

Animals↗

PubMed1985

Serum osteocalcin concentrations in children with metabolic bone disease.

We surveyed both normal children and patient populations to identify the effects of metabolic bone disease and impaired renal function on serum levels of osteocalcin, a vitamin K-dependent protein synthesized in bone. Cord blood osteocalcin was nearly double that of maternal osteocalcin, but there was no correlation between the two. Infants with Apgar scores less than or equal to 7 had a lower mean serum osteocalcin value (8.7 ng/ml, n = 8) than did those with scores of 8 to 10 (16.6 ng/ml, n = 38). Serum osteocalcin elevation coincided with the pubertal growth spurt. In boys, levels decreased to adult values by 18 years of age, as do other indices of bone metabolism; in girls, the levels decreased earlier and had a less pronounced maximum. In children with renal failure, osteocalcin was substantially increased, presumably because of diminished renal clearance of the protein. Children receiving peritoneal dialysis, however, had mean serum concentrations less than half of those seen in children receiving hemodialysis (117 vs 328 ng/ml). The peritoneal dialysate contained significant amounts of osteocalcin, but none was detectable in hemodialysate. Correlation between bone disease and serum osteocalcin was evident in a longitudinal study of one patient with renal failure. Children with various forms of rickets had elevated osteocalcin levels; hypoparathyroidism and osteoporosis were accompanied by variable changes. Serum osteocalcin holds promise as a useful marker of subacute changes in bone metabolism.

Adolescent↗

PubMed1993

Metal ion binding to dog osteocalcin studied by 1H NMR spectroscopy.

One-dimensional 1H NMR was employed to study the effects of Ca2+ and Lu3+ binding on the apo and calcium-saturated forms of dog bone Gla protein (BGP, osteocalcin). Titration of apo dog BGP with Ca2+ in 20 mM NaCl showed spectral perturbations consistent with the binding of 5 mol equiv of calcium in the NMR slow-exchange limit. The first 2 Ca2+ equiv induced significant conformational changes in the apoprotein, binding cooperatively with a Kd1 approximately 5.0 x 10(-4) M and a Hill coefficient H = 2.3 in 20 mM NaCl. The last 3 equiv bound with a slightly weaker affinity and did not induce significant structural changes. Neither the affinity nor the stoichiometry of calcium binding was significantly altered at 150 mM NaCl. The addition of only 1 Lu3+ equiv to apo dog osteocalcin was sufficient to induce the same spectral perturbations as 2 Ca2+ ions. The addition of 2 Lu3+ equiv to calcium-saturated osteocalcin had little effect on its 1H NMR spectrum, and BGP aggregated at [Lu3+]o/[BGP]o ratios greater than 2 in either the presence or absence of calcium. The spectrum of calcium-saturated osteocalcin was invariant at < or = 55 degrees C (< or = 50 degrees C in 150 mM NaCl), after which the proton resonances shifted to frequencies more characteristic of apo BGP. Saturation with calcium somewhat stabilized the apo dog osteocalcin protein against conformational changes induced at pH extremes; apo BGP was stable at 6.0 < or = pH < or = 10, and calcium-saturated BGP was stable at 5.8 < or = pH < or = 10. Both our NMR and gel filtration data indicate that calcium-saturated osteocalcin exists as a dimer at both high and low protein concentrations. A conformational change in dog osteocalcin was thus induced by the cooperative association of Ca2+ to two high-affinity sites on the protein and stabilized by the association of 3 additional Ca2+ equiv. The results of our temperature and calcium binding studies were consistent with an estimated Kd1 approximately 5.0 x 10(-4) M for the two high-affinity sites. Lutetium induced the same structural changes in osteocalcin as calcium, but the two high-affinity Ca2+ binding sites did not have equal affinities for Lu3+. The BGP:Ca2+ complex was unstable at the low pH conditions induced by osteoclasts during bone resorption, yet the osteocalcin protein retained a BGP:Ca(2+)-like conformation at low pH. However, unlike the calcium-saturated form of the protein, osteocalcin was monomeric at low pH.

Amino Acid Sequence↗

PubMed1992

Rat serum osteocalcin concentration is determined by food intake and not by inflammation.

Osteocalcin, or bone gla protein, is the major noncollagenous protein in bone. Previous findings of decreased serum osteocalcin concentrations in children with Kwashiorkor led us to analyze the respective influence of nutritional status and inflammation on circulating osteocalcin in growing rats. Food deprivation for 72 h induced a significant 24% decrease in serum osteocalcin. Refeeding produced a rapid rise in serum osteocalcin, which reached control concentrations after 24 h of refeeding. Bone osteocalcin was not affected by these dietary manipulations. The changes in serum osteocalcin were not correlated with serum 1,25-dihydroxycholecalciferol, whereas they could be related to serum 25-hydroxycholecalciferol concentrations. Turpentine injection reduced serum osteocalcin concentration, but pair-feeding showed that this decrease was entirely attributable to spontaneous food restriction and not to inflammation. By contrast, the sensitive nutritional marker, serum transthyretin, was affected by both inflammation and food restriction. These results indicate that serum osteocalcin is closely related to food intake but not to inflammation, suggesting that the dramatic decrease in serum osteocalcin that we previously observed in children with Kwashiorkor is due to malnutrition per se.

Animals↗

PubMed2005

Serum osteocalcin and CTX-MMP concentration in young exercising thoroughbred racehorses.

Bone responds to exercise with changes in bone (re-)modelling, which might be monitored non-invasively with biochemical bone markers. The aim of this study was to evaluate the influence of exercise on serum osteocalcin and serum carboxy-terminal cross-linked telopeptide of type I collagen generated by matrix metalloproteinases (CTX-MMP) concentration in young racehorses. Seventy-one 2 to 4-year-old Thoroughbreds were included in this prospective infield study. Blood sampling was performed six times (i.e. six sampling cycles) during a 9-month period. Serum samples were analysed with commercial osteocalcin and CTX-MMP radioimmunoassays. Two-year-old racehorses had higher serum osteocalcin and CTX-MMP values than 3-year-old horses. Gender and training amplitude did not significantly influence serum osteocalcin and CTX-MMP values. Two-year-old horses showed an increase in osteocalcin values between cycles 2 and 3 and an increase in serum CTX-MMP values between cycles 1 and 2. Serum osteocalcin and CTX-MMP concentrations decreased between cycles 4 and 5, and 5 and 6. Three-year-old horses showed an increase in serum osteocalcin levels between cycles 3 and 4 and an increase in serum CTX-MMP concentrations between cycles 1 and 2, and 3 and 4. Serum osteocalcin levels decreased between cycles 5 and 6, whereas serum CTX-MMP levels decreased between cycles 4 and 5, and 5 and 6. Two- and three-year-old horses showed a decreased osteocalcin/CTX-MMP ratio between cycles 1 and 2. Moreover, 2-year-old horses showed an increase in the osteocalcin/CTX-MMP ratio between cycles 2 and 3. Sore shin formation did not significantly influence serum osteocalcin and CTX-MMP values. Serum osteocalcin and CTX-MMP are promising bone markers for monitoring exercise induced changes in equine bone metabolism.

Age Factors↗

PubMed1992

Dose-dependent effects of aluminum on osteocalcin synthesis in osteoblast-like ROS 17/2 cells in culture.

This in vitro study evaluates the effect of aluminum (Al3+) on osteocalcin, a small protein that is produced by the osteoblast. After stimulation with various doses of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3; 10(-11) to 10(-9) M], osteocalcin was consistently lower in the culture medium of ROS 17/2 osteoblastic cells conditioned with 5 microM Al(3+)-saturated transferrin (AlTR) than in apotransferrin (ApoTR)-treated controls. In a second experiment, cultures were conditioned with various doses of AlTR or ApoTR (1.6-8.0 microM) and stimulated with 10(-9) M 1,25(OH)2D3. High doses of AlTR (4.8-8.0 microM) resulted in lower medium and unchanged intracellular content of osteocalcin than treatment with equal amounts of ApoTR. However, in the same experiment, lower doses of AlTR or ApoTR (1.6 and 3.2 microM) yielded different results, i.e., increased medium and intracellular contents of osteocalcin in the Al(3+)-treated cells. Expression of osteocalcin mRNA was not altered in cultures conditioned with low (1.6 microM) or high (8.0 microM) concentrations of AlTR or ApoTR. Similarly, no effect of Al3+ was observed on total protein content, the rate of total protein synthesis, and the degradation of secreted osteocalcin in cultures conditioned with various doses of AlTR or ApoTR. These findings suggest that AlTR affects osteocalcin synthesis in a specific manner, without concomitant effects on the rate of total protein synthesis or on the rate of degradation of osteocalcin. This effect is dose dependent, i.e., low doses of AlTR stimulate and high doses suppress osteocalcin synthesis and/or secretion, and it appears to be posttranscriptional, since the expression of osteocalcin mRNA is not affected.

Aluminum↗

PubMed2005

Human osteocalcin and bone sialoprotein mediating osteomimicry of prostate cancer cells: role of cAMP-dependent protein kinase A signaling pathway.

Osteocalcin and bone sialoprotein are the most abundant noncollagenous bone matrix proteins expressed by osteoblasts. Surprisingly, osteocalcin and bone sialoprotein are also expressed by malignant but not normal prostate epithelial cells. The purpose of this study is to investigate how osteocalcin and bone sialoprotein expression is regulated in prostate cancer cells. Our investigation revealed that (a) human osteocalcin and bone sialoprotein promoter activities in an androgen-independent prostate cancer cell line of LNCaP lineage, C4-2B, were markedly enhanced 7- to 12-fold in a concentration-dependent manner by conditioned medium collected from prostate cancer and bone stromal cells. (b) Deletion analysis of human osteocalcin and bone sialoprotein promoter regions identified cyclic AMP (cAMP)-responsive elements (CRE) as the critical determinants for conditioned medium-mediated osteocalcin and bone sialoprotein gene expression in prostate cancer cells. Consistent with these results, the protein kinase A (PKA) pathway activators forskolin and dibutyryl cAMP and the PKA pathway inhibitor H-89, respectively, increased or repressed human osteocalcin and bone sialoprotein promoter activities. (c) Electrophoretic mobility shift assay showed that conditioned medium-mediated stimulation of human osteocalcin and bone sialoprotein promoter activities occurs through increased interaction between CRE and CRE-binding protein. (d) Conditioned medium was found to induce human osteocalcin and bone sialoprotein promoter activities via increased CRE/CRE-binding protein interaction in a cell background-dependent manner, with marked stimulation in selected prostate cancer but not bone stromal cells. Collectively, these results suggest that osteocalcin and bone sialoprotein expression is coordinated and regulated through cAMP-dependent PKA signaling, which may define the molecular basis of the osteomimicry exhibited by prostate cancer cells.

Base Sequence↗

PubMed1987

Clearance of osteocalcin by peritoneal dialysis in children with end-stage renal disease.

Osteocalcin is a bone-specific protein whose concentration in blood is a direct reflection of bone turnover. In chronic renal failure, circulating osteocalcin is elevated. This elevation is due to decreased renal clearance and, in some patients, increased bone turnover secondary to renal osteodystrophy. In children receiving continuous ambulatory peritoneal dialysis, mean serum osteocalcin concentrations are substantially lower than in similar patients on hemodyalysis (1). This difference may be due to clearance of the protein by the peritoneal membrane. To test this possibility we examined osteocalcin in 16 infants and adolescents undergoing continuous ambulatory peritoneal dialysis with two commercially available glucose-based dialysis solutions (2.5 and 4.25% Dianeal). Mass transfer of osteocalcin over 5-h dialysis exchange periods was -18.9 +/- 2.8 and -28.4 +/- 7.8 micrograms for the low and high glucose solutions, respectively. Serum levels fell over the course of single exchange periods in concert with increasing dialysate concentrations. There were significant correlations between initial blood concentrations of osteocalcin and the total amount of osteocalcin transferred (r = 0.609 and 0.642 for the high and low glucose solutions, respectively, p less than 0.05). There were also strong correlations between the mass transfers of osteocalcin and those of creatinine (p less than 0.05) and total protein (p less than 0.01) with the 4.25% glucose exchange. The relationships were weaker with the 2.5% glucose exchange. Fractionation of serum revealed a single immunoreactive peak eluting coincident with intact osteocalcin, but two or three immunoreactive peaks were identified in matching dialysate samples, suggesting that both intact osteocalcin and circulating fragments are transferred by the peritoneal membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1990

Osteopetrosis in the rat: coexistence of reductions in osteocalcin and bone resorption.

Osteocalcin, one of the vitamin K-dependent bone proteins, has recently been implicated in bone resorption. To explore this hypothesis, bone and serum osteocalcin were measured in three different osteopetrotic rat mutations characterized by reduced bone resorption. These three mutations (ia/ia, tl/tl, and op/op) exhibit heterogeneity with respect to osteoclast number and activity and response to being cured by bone marrow transplantation. Calvarial bone osteocalcin was present in normal amounts, but difficult to extract, in ia/ia rats that have increased numbers of inactive osteoclasts. Bone osteocalcin was greatly decreased in op/op (53-60% of control) and tl/tl (64-73% of control) osteopetrotic rats, in which osteoclasts are both reduced in number and inactive. These decreases in osteocalcin levels in bone coexist with elevated serum levels of osteocalcin in all three mutations. Since osteocalcin synthesis is known to be stimulated by 1,25(OH)2D3, the increase in serum osteocalcin may be a reflection of the elevated blood levels of 1,25(OH)2D3 known to occur in each of these mutations. These findings indicate that the composition of osteopetrotic bone is abnormal with respect to osteocalcin in the two rat osteopetrotic mutations showing decreased osteoclast numbers. Considered together with the emerging evidence that the extracellular matrix in many developing tissues plays a role in cell recruitment and differentiation, these data suggest that osteocalcin abnormalities may be a contributing factor to the spectrum of osteoclast aberrations in osteopetrosis.

Aging↗

PubMed1987

Serum osteocalcin in Paget's disease of bone: basal concentrations and response to bisphosphonate treatment.

Serum osteocalcin concentrations were measured in 42 patients with Paget's disease of bone and elevated serum alkaline phosphatase (AP) levels. High serum osteocalcin levels were found in only 22 patients. Serum osteocalcin was significantly correlated with urinary hydroxyproline excretion (r = 0.747; P less than 0.001) and, to a lesser extent, with serum AP levels (r = 0.483; P less than 0.01). In 23 patients who were followed during treatment with iv (3-amino-1-hydroxypropylidene) 1,1-bisphosphonate (APD) for 10 days, a dissociation among these 3 biochemical parameters was found. Urinary hydroxyproline excretion fell significantly (P less than 0.001), serum AP levels decreased, but not significantly, and serum osteocalcin concentrations increased progressively (P less than 0.001). This increase was greater when initial levels were lower than expected for the activity of the disease. The rise in serum osteocalcin correlated significantly with the concomitant increase in serum 1,25-dihydroxyvitamin D concentrations. Three months after initiation of treatment, all 3 parameters, urinary OHP excretion, serum AP, and serum osteocalcin levels, were near or within the normal range. These results indicate that serum osteocalcin is not a clinically useful parameter for assessment of the activity of Paget's disease. Its basal concentrations lag behind those expected from the activity of the disease, suggesting defective osteocalcin production. It appears that the functions of osteocalcin and AP as well as their initial expression by the osteoblasts are different and that this difference may be important for the quality of bone formed in Paget's disease. APD can modulate the release of osteocalcin, possibly through stimulation of 1,25-dihydroxyvitamin D production, although other factors may be involved.

Adult↗

PubMed1991

Acute changes in serum osteocalcin during induced hypocalcemia in humans.

Although levels of serum osteocalcin are thought to be an indicator of osteoblastic activity and bone formation, there is little information regarding the acute effects of changes in calcium or PTH levels on circulating osteocalcin concentrations. To study the effect of stepwise decreases in ionized calcium (CaI) on osteocalcin levels, we infused six normal subjects with citrate for four 30-min intervals using two different protocols. One protocol (pulse infusion) used alternating rates of infusion and resulted in rapid stepwise decrements in serum CaI. The second protocol (continuous infusion) used constant intermediate rates of citrate infusion and produced slower decrements in CaI, but with similar changes in magnitude. We monitored serum CaI, intact PTH, and osteocalcin concentrations during the course of these infusions. During each step of the pulse infusion the osteocalcin responses to changes in CaI in general were parallel to the changes in PTH (r = 0.462; P = 0.02) and were inversely correlated to CaI (r = -0.562; P = 0.003). The osteocalcin concentrations at the end of each 30-min period were higher than at the beginning of that period; over the total 120 min, osteocalcin levels rose from 3.46 +/- 0.63 to 6.88 +/- 1.08 micrograms/L (P less than 0.05). In contrast, during the first two periods of the continuous infusion, osteocalcin concentrations changed slightly. Only during the last two periods of the continuous infusion did osteocalcin respond in a manner characteristic of that observed with the pulse infusion. These data indicate that osteocalcin concentrations in the circulation may be acutely regulated by calcium and/or PTH.

Adult↗