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PubMed2004

Osteocalcin synthesis by human osteoblasts from normal and osteoarthritic bone after vitamin D3 stimulation.

Alterations in osteoblast metabolism are involved in the pathogenesis of typical subchondral bone changes in osteoarthritis (OA). Osteocalcin is a specific bone protein, synthesised by the osteoblasts, which can be considered a marker of metabolic activity of these cells. In this study we correlated osteocalcin production from human osteoblasts isolated from healthy and osteoarthritic subjects to the degree of cartilage damage, before and after stimulation with 1,25(OH)2-vitamin D3, the active metabolite of vitamin D3. We isolated human osteoblasts from cancellous bone of healthy subjects and from subchondral bone of osteoarthritic subjects and considered the osteoblasts corresponding to different degrees of cartilage damage as different cell populations. We determined the osteocalcin production in normal and osteoarthritic osteoblasts from maximal and minimal cartilage damage areas both under basal conditions and after vitamin D3 stimulation. Compared to normal osteoblasts, under basal conditions osteocalcin production is significantly greater in osteoarthritic osteoblasts, corresponding both to maximal and minimal damage joint areas. No differences were observed between osteoblasts from maximal and minimal damage areas. The response of osteoblasts to vitamin D3 stimulation appeared to be proportional to the degree of joint damage, as the vitamin D3-induced increase in osteocalcin is proportionally greater in maximally damaged osteoblasts compared to minimally damaged ones. Thus, after vitamin D3 stimulation, a significant increase in osteocalcin production by maximally damaged osteoblasts compared to the minimally damaged ones was observed. This study confirms abnormal osteoarthritic osteoblast behaviour and indicates that osteoblasts from different areas of the same affected joint may be metabolically different, supporting the hypothesis that subchondral osteoblasts may play an essential role in the pathogenesis of OA.

Aged↗
PubMed2005

Adenylyl cyclase-cAMP system inhibits thyroid hormone-stimulated osteocalcin synthesis in osteoblasts.

It is generally recognized that thyroid hormone modulates osteoblast cell function. We have previously shown that triiodothyronine (T(3)) activates p38 mitogen-activated protein (MAP) kinase, resulting in the synthesis of osteocalcin in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effect of the adenylyl cyclase-cAMP system on thyroid hormone-stimulated osteocalcin synthesis in these cells. Dibutyryl-cAMP (DBcAMP) reduced the osteocalcin synthesis stimulated by T(3). Forskolin and cholera toxin suppressed the osteocalcin synthesis while dideoxyforskolin, a forskolin derivative that does not activate adenylyl cyclase, had little effect on the synthesis. KT5720, a selective inhibitor of protein kinase A, reversed the inhibitory effect of forskolin or DBcAMP. DBcAMP and forskolin markedly reduced the phosphorylation of p38 MAP stimulated by T(3). Pituitary adenylate cyclase-activating polypeptide (PACAP) significantly inhibited the T(3)-stimulated osteocalcin synthesis. These results strongly suggest that the adenylyl cyclase-cAMP system has an inhibitory role in thyroid hormone-stimulated osteocalcin synthesis via suppression of p38 MAP kinase activation in osteoblasts.

Adenylyl Cyclases↗
PubMed1990

Abnormalities in serum osteocalcin values in children with chronic rheumatic diseases.

We studied bone mineral metabolism prospectively in 113 children with chronic rheumatic diseases (juvenile arthritis, systemic lupus erythematosus, and juvenile dermatomyositis) to determine the relationship of serum levels of osteocalcin to rheumatic disease activity and corticosteroid usage, and to determine, in part, the cause of osteopenia in this population. Disease activity was quantitated by historical, clinical, and serologic means and an activity score derived. The 113 children were divided according to the expression of their disease, which was active (group 1: mean score 3.42, mean erythrocyte sedimentation rate 28 mm/hr) or inactive (group 2: score 1.7, erythrocyte sedimentation rate 15 mm/hr) (p less than 0.02 group 1 vs group 2 for each value), or which remitted during the study (group 3). We found that serum levels of osteocalcin, but not those of ionized calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and parathyroid hormone, were reduced in group 1 children even before corticosteroid therapy was employed. Children in both group 2 and group 3 had normal osteocalcin levels despite the use of corticosteroids. The reduced levels of osteocalcin were predictive of a reduction in bone mass measured by photon absorptiometry in 16 of 19 children so studied. We conclude that skeletal abnormalities that result in a reduced bone mass occur in the clinical course of the majority of children with active chronic rheumatic diseases, are associated with reduced osteocalcin levels, and are not related to the use of corticosteroids. Serum osteocalcin levels may be a sensitive marker for reduced osteoblast activity and bone formation in children with chronic rheumatic diseases.

Adolescent↗
PubMed1988

Plasma osteocalcin levels in stone disease. A potential aid in the differential diagnosis of calcium nephrolithiasis.

Plasma osteocalcin levels were measured by radioimmunoassay in 70 consecutive patients with recurrent calcium (sterile) nephrolithiasis during diagnostic evaluation for the cause of the disease. Nephrogenous cyclic adenosine 3,5'-monophosphate levels also were measured in most of the subjects. Included in the sampling, as determined by standard diagnostic criteria, were 12 patients with absorptive hypercalciuria type I, 15 with absorptive hypercalciuria type II, 22 with renal leak hypercalciuria, 11 with normocalciuria, 6 with primary hyperparathyroidism, 3 with renal tubular acidosis and 1 with Paget's disease, as well as 12 control subjects. The observed plasma osteocalcin levels (ng. per ml. mean +/- standard error) were absorptive hypercalciuria I 2.6 +/- 0.20, absorptive hypercalciuria II 3.1 +/- 0.21, renal hypercalciuria 8.7 +/- 0.45, normocalciuric nephrolithiasis 3.3 +/- 0.25, primary hyperparathyroidism 13.2 +/- 0.91, renal tubular acidosis (range) 5.2 to 10.6, Paget's disease 18.0 and control 3.1 +/- 0.20. There were significant differences between the plasma osteocalcin levels of renal hypercalciuria versus primary hyperparathyroidism and renal hypercalciuria/primary hyperparathyroidism versus any other group. There was good correlation between plasma osteocalcin and cyclic adenosine 3,5'-monophosphate data (correlation coefficient 0.72, p less than 0.005). Plasma osteocalcin levels are a potential differential diagnostic tool for patients with stone disease. The diagnostic value compares favorably with that of cyclic adenosine 3,5'-monophosphate, with the advantage that the determination of plasma osteocalcin requires only a single test.

Adult↗
PubMed1998

Increases in osteocalcin after ovariectomy are amplified by LPS injection: strain differences in bone remodelling.

1. LPS (Escherichia coli serotype 0111:B4, 300 micrograms/mouse IP) increases serum osteocalcin in normal female C57B16 mice from 2 to 6 hr after its injection, with peak levels at 2-4 hr after LPS. 2. Both basal and LPS-stimulated serum osteocalcin were markedly inhibited by dexamethasone (10 mg/kg IP). 3. When observed 3 hr after LPS injection, serum osteocalcin was increased by ovariectomy (OVX) (with respect to sham-operated mice) and this increase was amplified in LPS-treated mice. This increase in osteocalcin was maximal 14 days after OVX, whereas urinary deoxypyridinoline cross-link levels were increased at all observation times (11-28 days). 4. All these changes were also observed in Balb/c mice but their magnitudes were consistently lower than those in C57B16 mice. 5. We propose that, (1) osteocalcin is a useful marker of bone remodelling in mice and the precision of measurement of changes in its levels after OVX is increased by LPS treatment and (2) C57B16 mice give greater magnitude and more consistent changes in both serum osteocalcin and urinary deoxypyridinoline cross-links after OVX, and may be a better strain for development of an in vivo model of post-menopausal osteoporosis.

Animals↗
PubMed2002

Sphingomyelinase amplifies BMP-4-induced osteocalcin synthesis in osteoblasts: role of ceramide.

We previously reported that extracellular sphingomyelinase induces sphingomyelin hydrolysis in osteoblast-like MC3T3-E1 cells and that mitogen-activated protein (MAP) kinases are involved in bone morphogenetic protein (BMP)-4-stimulated osteocalcin synthesis in these cells. In the present study, we investigated whether sphingomyelinase affects BMP-4-stimulated synthesis of osteocalcin in osteoblast-like MC3T3-E1 cells. Sphingomyelinase significantly enhanced the BMP-4-stimulated osteocalcin synthesis. Among sphingomyelin metabolites, C(2)-ceramide enhanced the BMP-4-stimulated osteocalcin synthesis while sphingosine and sphingosine 1-phosphate had little effect on the synthesis. D-erythro-MAPP, an inhibitor of ceramidase, amplified the sphingomyelinase-effect on the osteocalcin synthesis. C(2)-ceramide suppressed the BMP-4-induced phosphorylation of p44/p42 MAP kinase, while having little effect on the phosphorylation of Smad1 and p38 MAP kinase. Taken together, our results strongly suggest that extracellular sphingomyelinase enhances the BMP-stimulated osteocalcin synthesis via ceramide in osteoblasts and that the effect of ceramide is exerted at a point upstream from p44/p42 MAP kinase.

Amidohydrolases↗
PubMed2002

Influence of osteocalcin and collagen I on the mechanical and biological properties of Biocement D.

In order to generate a calcium-phosphate bone cement as a transient replacement for bone defects, we modified Biocement D (Merck Biomaterial GmbH) containing mineralised collagen with osteocalcin, the most abundant non-collageneous protein of bone. Osteocalcin was added to the cement paste during setting in order to control the crystallisation kinetics of hydroxyapatite (HAP) as well as to stimulate the interaction of osteoblasts and osteoclasts with the bone replacement material. Analysis by SEM and AFM shows, that the addition of osteocalcin causes a nanosize microstructure of the calcium cement, which can be explained by inhibited growth of HAP crystals. The fracture strength of the material decreased by incorporation of osteocalcin, pointing onto a higher defect concentration of the crystalline structure. The impact of osteocalcin onto the interaction of bone cells with HAP-Collagen I-cements was studied in a cell culture system using the human osteosarcoma cell line SAOS-2. Results suggest, that osteocalcin might possibly improve the initial adherence of osteoblast-like cells, whereas proliferation of the cells is not effected.

Biomechanical Phenomena↗
PubMedDate not supplied

Differential expression of dentin matrix protein 1, type I collagen and osteocalcin genes in rat developing mandibular bone.

The expression of dentin matrix protein 1 (Dmp1) mRNA has been compared with that of type I collagen and osteocalcin mRNAs during bone formation in the rat mandible, using in situ hybridization. At embryonic day 15 (E15), type I collagen and osteocalcin mRNAs were expressed by the majority of newly-differentiated osteoblasts attached to unmineralized bone matrices, whereas Dmp1 mRNA expression was confined to only a few osteoblasts. Expression of these genes increased as the number of osteoblasts increased in specimens from E16 to E18. At E20, expression of Dmp1, type I collagen and osteocalcin was also observed in osteocytes. Dmp1 expression continued in osteocytes as they matured up to the 90-day-old specimens, whereas type I collagen and osteocalcin expression in osteocytes almost disappeared at 30 days of postnatal life. In contrast, osteoblasts continued to express type I collagen and osteocalcin in 90-day-old rats, but transiently expressed Dmp1 mRNA, which was seen in the minority of osteoblasts at 14 days of postnatal life. These data show that the developmental expression patterns of Dmp1 in osteogenic differentiation differ from those of type I collagen and osteocalcin, and Dmp1 appears to be expressed by osteocytes throughout ossification in the skeleton. These observations indicate that Dmp1 may serve unique biological functions in osteocyte and bone metabolism.

Animals↗
PubMed2006

Methionine synthase reductase polymorphisms are associated with serum osteocalcin levels in postmenopausal women.

Homocysteine (Hcy) is thought to play an important role in the development of osteoporosis and fracture. Methionine synthase reductase (MTRR) is an enzyme involved in the conversion of Hcy to methionine. We hypothesized that certain genetic polymorphisms of MTRR leading to reduced enzyme activity may cause hyperhomocysteinemia and affect bone metabolism. We therefore examined the associations of the A66G and C524T polymorphisms of the MTRR gene with bone mineral density (BMD) and serum osteocalcin levels in postmenopausal women. Although we did not detect any significant associations between MTRR polymorphisms and BMD or serum osteocalcin levels, we found that the 66G/524C haplotype, which has reduced enzyme activity, was significantly associated with serum osteocalcin levels in a gene-dose dependent manner (P = 0.002). That is, the highest osteocalcin levels (34.5 +/- 16.8 ng/ml) were observed in subjects bearing two copies, intermediate osteocalcin levels (32.6 +/- 14.4 ng/ml) were observed in subjects bearing one copy, and the lowest levels of osteocalcin (28.8 +/- 10.9 ng/ml) were observed in subjects bearing no copies. These results suggest that the 66G/524C haplotype of the MTRR gene affect bone turn over rate.

Aged↗
PubMed2002

Osteocalcin and myoglobin removal in on-line hemodiafiltration versus low- and high-flux hemodialysis.

BACKGROUND: Removal of medium and large solutes is poor with low-flux (LF-HD) and limited with high-flux hemodialysis (HF-HD) and on-line hemodiafiltration (OL-HDF). In clinical practice, there are few in vivo solute markers. Osteocalcin is a protein with a molecular mass of 5,800 daltons, and myoglobin is a large molecule with a molecular mass of 17,200 daltons. The aim of this study was to evaluate the impact of OL-HDF on in vivo removal of a wide spectrum of solutes (urea, creatinine, osteocalcin, beta2-microglobulin, and myoglobin) in comparison to LF-HD and HF-HD. METHODS: Twenty-three patients (15 men, 8 women) were studied. Every patient underwent three dialysis sessions with routine HD parameters. We compared 1.8-m2 polysulfone LF-HD and 1.8-m2 polysulfone HF-HD versus OL-HDF. Predialysis and postdialysis solute concentrations were measured. The percentage of reduction ratio for each solute was calculated. RESULTS: Mean values for predialysis osteocalcin, beta2-microglobulin, and myoglobin were 16.3 +/- 21 ng/mL, 27.4 +/- 5 mg/L, and 239 +/- 162 ng/mL in LF-HD, respectively. Urea and creatinine reduction ratios were similar in LF-HD and HF-HD and only 1.2% higher in OL-HDF. Osteocalcin, beta2-microglobulin, and myoglobin reduction ratios for LF-HD were negligible. Mean osteocalcin reduction rates were 54.2% +/- 12% for HF-HD versus 63.5% +/- 9% for OL-HDF (reinfusion volume, 26.8 +/- 5 L/session; P < 0.01). Mean beta2-microglobulin reduction rates were 60.1% +/- 9% for HF-HD versus 75.4% +/- 9% for OL-HDF (P < 0.01). Mean myoglobin reduction rates were 24.5% +/- 6% and 62.7% +/- 9% for HF-HD and OL-HDF, respectively (P < 0.01). CONCLUSION: LF-HD does not seem to remove solutes with a molecular weight greater than 5,800 daltons. OL-HDF provides marked enhancement of convection volume and enables a significant increase in osteocalcin and beta2-microglobulin removal. Myoglobin extraction is nil with LF-HD, very low with HF-HD, and only adequate with OL-HDF.

Adult↗
PubMed1994

Serum osteocalcin concentrations in diabetic pregnant women and their newborns.

Osteocalcin and PTH serum levels were measured in 41 insulin-dependent diabetic pregnant women through the three trimesters of pregnancy with a total of 106 determinations of osteocalcin and 137 of PTH. In parallel we quantified these parameters in 90 normal pregnant women throughout the three trimesters of pregnancy. In addition calcitriol, osteocalcin and PTH levels were quantified at delivery in 16 diabetic pregnant women and 16 normal pregnant women at delivery, in cord serum and in the infants during the first days of life. Non-pregnant women (n = 48) were the control group. In normal pregnant women PTH levels increased during the third trimester and total calcitriol increased at delivery. Osteocalcin levels decreased in the second trimester but returned to normal values during the third trimester of pregnancy. Diabetic pregnant women showed constant PTH levels throughout pregnancy. At delivery in diabetic pregnant women, total calcitriol levels increased to a smaller extent than in normal pregnant women. Osteocalcin concentrations in the second and third trimester of pregnancy were lower than in the non-pregnant group. Infants of diabetic mothers showed lower PTH and osteocalcin concentrations than infants of normal pregnant women, whereas their calcitriol levels were similar. These data indicate that diabetes decreases bone turnover during pregnancy in the mother and during the perinatal period in their offspring.

Adult↗
PubMed1992

Dynamics of circulating osteocalcin in rats during growth and under experimental conditions.

Osteocalcin is the most abundant non-collagenous protein produced in the process of bone formation. A specific radioimmunoassay has been developed using a rabbit antiserum raised against osteocalcin extracted from rat bone. The sensitivity of the assay was tested in male and female rats under different experimental conditions: ovariectomy led to a mild increase in circulating osteocalcin (70.6 +/- 6.9 vs 51.6 +/- 6.3 ng/ml; p < 0.05) and deprivation of dietary calcium elevated plasma levels further (119 +/- 6.3 ng/ml; p < 0.01). As expected, pharmacological enhancement of bone turnover with calcitriol produced a significant increase in plasma osteocalcin (296 +/- 24.1 vs 89.5 +/- 5.1 ng/ml; p < 0.01), whereas prednisolone, a steroidal compound known to inhibit osteoid mineralization, significantly reduced circulating concentrations of this protein (70 +/- 7.4 vs 100 +/- 6.3 ng/ml; p < 0.05). Plasma kinetics recorded in female rats between birth and the 100th week revealed a highly significant (p < 0.001) elevation peaking at the third week (231 +/- 70.6 ng/ml) and slowly declining to reach values measured at birth (41.3 +/- 9.2 ng/ml) at the 16th week (47 +/- 4.6 ng/ml). Subsequently, a small but significant (p < 0.05) decline towards senescence was recorded. The osteocalcin surge preceded the period of rapid growth (weeks 3 to 11) estimated by vertebral length progression, showing a tendency to stabilize as growth spurt slowed down. A moderate but significant (p < 0.01) increment was observed after mating (87.8 +/- 5.1 vs 69.5 +/- 4.0 ng/ml). Although plasma osteocalcin remained stable during lactation, average levels were elevated in comparison with age-matched non-pregnant controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1994

Transcriptional control of the tissue-specific, developmentally regulated osteocalcin gene requires a binding motif for the Msx family of homeodomain proteins.

The OC box of the rat osteocalcin promoter (nt -99 to -76) is the principal proximal regulatory element contributing to both tissue-specific and developmental control of osteocalcin gene expression. The central motif of the OC box includes a perfect consensus DNA binding site for certain homeodomain proteins. Homeodomain proteins are transcription factors that direct proper development by regulating specific temporal and spatial patterns of gene expression. We therefore addressed the role of the homeodomain binding motif in the activity of the OC promoter. In this study, by the combined application of mutagenesis and site-specific protein recognition analysis, we examined interactions of ROS 17/2.8 osteosarcoma cell nuclear proteins and purified Msx-1 homeodomain protein with the OC box. We detected a series of related specific protein-DNA interactions, a subset of which were inhibited by antibodies directed against the Msx-1 homeodomain but which also recognize the Msx-2 homeodomain. Our results show that the sequence requirements for binding the Msx-1 or Msx-2 homeodomain closely parallel those necessary for osteocalcin gene promoter activity in vivo. This functional relationship was demonstrated by transient expression in ROS 17/2.8 osteosarcoma cells of a series of osteocalcin promoter (nt -1097 to +24)-reporter gene constructs containing mutations within and flanking the homeodomain binding site of the OC box. Northern blot analysis of several bone-related cell types showed that all of the cells expressed msx-1, whereas msx-2 expression was restricted to cells transcribing osteocalcin. Taken together, our results suggest a role for Msx-1 and -2 or related homeodomain proteins in transcription of the osteocalcin gene.

Animals↗
PubMed1997

Transglutaminase-catalyzed cross-linking of osteopontin is inhibited by osteocalcin.

Osteocalcin, the most abundant noncollagenous protein of bone matrix, has been demonstrated to inhibit bone growth by gene knockout experiments (Ducy, P., Desbois, C., Boyce, B., Pinero, G., Story, B., Dunstan, C., Smith, E., Bonadio, J., Goldstein, S., Gundberg, C., Bradley, A., and Karsenty, G. (1996) Nature 382, 448-452). Its specific functional mechanism in bone metabolism is, however, largely unknown. In this study, we provide evidence that osteocalcin has an inhibitory effect on tissue transglutaminase activity, as measured by cross-linking of osteopontin, another bone matrix protein. Using a set of synthetic peptides, we found that the inhibitory activity resided within the first 13 N-terminal amino acid residues of osteocalcin. An N-terminal peptide also inhibited cross-linking of another tissue transglutaminase substrate, beta-casein. The inhibitory peptide was shown to have affinity for the substrates of transglutaminase rather than for the enzyme. Since the N terminus of osteocalcin exhibits homology to the substrate recognition site sequences of two transglutaminases, we conclude that the inhibitory effect is most likely due to competition with the enzyme for the transglutaminase-binding region of the substrates, osteopontin and beta-casein, which prevents access of the enzyme to them to perform its function. The interference of osteocalcin with osteopontin cross-linking gives osteocalcin a new potential function as the first protein inhibitor of tissue transglutaminase. This suggests a specific role and a plausible mechanism for it as a modulator of maturation, stabilization, and calcification of bone matrix.

Amino Acid Sequence↗
PubMed1998

Functional hierarchy between two OSE2 elements in the control of osteocalcin gene expression in vivo.

Osteocalcin gene expression is initiated perinatally and is restricted to mature osteoblasts and odontoblasts. Because their pattern of expression is highly restricted, the osteocalcin genes are excellent tools to study osteoblast-specific gene expression. To define the mechanisms of osteocalcin cell-specific gene expression in vivo, we generated transgenic mice harboring deletion mutants of the promoter region of OG2, one of the mouse osteocalcin genes. We show here that only 647 base pairs of this promoter are sufficient to confer cell-specific and time-specific expression to a reporter gene in vivo. This promoter fragment contains two copies of OSE2. This osteoblast-specific cis-acting element binds Osf2, a recently characterized osteoblast-specific transcription factor (Ducy, P., Zhang, R., Geoffroy, V., Ridall, A. L., and Karsenty, G. (1997) Cell 89, 747-754). We also demonstrate that the proximal OSE2 element is critical to confer an osteoblast-specific, developmentally regulated pattern of expression to a reporter gene. The other OSE2 element, located more upstream and presenting a lower affinity for Osf2, affects only weakly OG2 promoter activity. These data demonstrate the crucial role of Osf2 in controlling osteocalcin gene expression. Since osteocalcin synthesis is a hallmark of the differentiated osteoblast phenotype, these results suggest that, beyond its developmental function, Osf2 is also required for the maintenance of the osteoblast phenotype postnatally.

Animals↗
PubMed2003

Activation of peroxisome proliferator-activated receptor-gamma inhibits the Runx2-mediated transcription of osteocalcin in osteoblasts.

Mesenchymal cells are able to differentiate into several distinct cell types, including osteoblasts and adipocytes. The commitment to a particular lineage may be regulated by specific transcription factors. Peroxisome proliferator-activated receptor-gamma (PPARgamma), acting in conjunction with CCAAT/enhancer-binding protein-alpha, has been suggested as a key regulator of adipogenic differentiation. Previous studies have shown that the activation of PPARgamma in osteoblasts suppresses osteoblast differentiation and the expression of osteocalcin, an osteoblast-specific protein. However, the mechanism of this inhibition remains unclear. We investigated the effect of PPARgamma activation on the expression of osteocalcin and analyzed the molecular mechanism. Mouse osteoblastic MC3T3-E1 cells expressed PPARgamma, which was transcriptionally active, whereas rat osteosarcoma ROS 17/2.8 cells did not. Treatment of MC3T3-E1 osteoblasts and ROS 17/2.8 cells stably transfected with PPARgamma2 with the PPARgamma activator 15-deoxy-Delta12,14-prostaglandin J2 inhibited the mRNA expression of osteocalcin and Runx2, the latter of which is a key transcription factor in osteoblast differentiation. This decreased expression of osteocalcin and Runx2 was partly explained by the decreased level of Runx2 resulting from the suppressed transcription from the Runx2 promoter. However, in addition to this indirect effect, the activation of PPARgamma by 15-deoxy-Delta12,14-prostaglandin J2 directly suppressed the Runx2-mediated induction of the activities of the osteocalcin promoter and the artificial promoter p6OSE2, which contains six tandem copies of osteoblast-specific element-2, the Runx2-binding promoter sequence. This inhibition was mediated by a physical interaction between PPARgamma and Runx2 and the subsequent repression of the transcriptional activity at the osteoblast-specific element-2 sequence. Thus, this study demonstrates that the activation of PPARgamma inhibits osteocalcin expression both by suppressing the expression of Runx2 and by interfering with the transactivation ability of Runx2.

Animals↗
PubMed2006

Identification of an osteocalcin isoform in fish with a large acidic prodomain.

Osteocalcin is a small, secreted bone protein whose gene consists of four exons. In the course of analyzing the structure of fish osteocalcin genes, we recently found that the spotted green pufferfish has two possible exon 2 structures, one of 15 bp and the other of 324 bp. Subsequent analysis of the pufferfish cDNA showed that only the transcript with a large exon 2 exists. Exon 2 codes for the osteocalcin propeptide, and exon 2 of pufferfish osteocalcin is approximately 3.4-fold larger than exon 2 previously found in other vertebrate species. We have termed this new pufferfish osteocalcin isoform OC2. Additional studies showed that the OC2 isoform is restricted to a unique fish taxonomic group, the Osteichthyes; OC2 is the only osteocalcin isoform found so far in six Osteichthyes species, whereas both OC1 and OC2 isoforms coexist in zebrafish and rainbow trout. The larger size of the OC2 propeptide is due to an acidic region that is likely to be highly phosphorylated and has no counterpart in the OC1 propeptide. We propose 1) that OC1 and OC2 are encoded by distinct genes that originated from a duplication event that probably occurred in the teleost fish lineage soon after divergence from tetrapods and 2) that the novel OC2 propeptide could be, if secreted, a phosphoprotein that participates in the regulation of biomineralization through its large acidic and phosphorylated propeptide.

Amino Acid Sequence↗
PubMed2000

Vitamin K supplementation reduces serum concentrations of under-gamma-carboxylated osteocalcin in healthy young and elderly adults.

BACKGROUND: Subclinical vitamin K insufficiency, manifested by under-gamma-carboxylation of the bone matrix protein osteocalcin, may be common. OBJECTIVE: Our objective was to delineate the prevalence of submaximal gamma-carboxylation as assessed by response to phylloquinone supplementation and to evaluate the effect of this intervention on skeletal turnover in healthy North American adults. DESIGN: Healthy subjects (n = 219), approximately equally distributed by sex and age (18-30 y and >/=65 y), received daily phylloquinone (1000 microg) or placebo for 2 wk. Serum undercarboxylated osteocalcin (ucOC) and total osteocalcin, N:-telopeptides of type I collagen (NTx), bone-specific alkaline phosphatase (BSAP), and phylloquinone concentrations were measured at baseline and after weeks 1 and 2. RESULTS: At baseline, the mean serum phylloquinone concentration was lower in the young than in the old group; there was no effect of sex. Concomitantly, baseline %ucOC was highest in the young and lowest in the old men (P: < 0.0001) but did not differ significantly by age in women. After supplementation, serum phylloquinone concentration increased approximately 10-fold (P: < 0.0001) at week 1 (from 0.93 +/- 0.08 to 8.86 +/- 0.70 nmol/L, x+/- SEM); this was sustained through week 2. Among all supplemented groups, mean %ucOC decreased from 7.6% to 3. 4% without significant differences by age or sex; 102 of 112 subjects had a >1% decrease. Phylloquinone supplementation reduced serum osteocalcin but did not alter NTx or BSAP concentration. CONCLUSIONS: Usual dietary practices in this population did not provide adequate vitamin K for maximal osteocalcin carboxylation. Phylloquinone supplementation reduced serum osteocalcin concentration but did not alter other markers of serum bone turnover.

Adolescent↗