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Biomedical subjects

A Mahonen

Publications and source records attributed to A Mahonen.

At least 19 recordsLinked to original sources
PubMed2004

Glucocorticoids induce glutamine synthetase expression in human osteoblastic cells: a novel observation in bone.

Glucocorticoids have marked effects on bone metabolism, and continued exposure of skeletal tissue to excessive amounts of these steroids results in osteoporosis. Therefore, in the present proteomic study, we characterized the potential effects of glucocorticoids on protein expression in human osteoblastic cells. Using two-dimensional gel electrophoresis and mass spectrometry, we identified an increased expression of glutamine synthetase (GS) in dexamethasone (Dex)-treated human MG-63 osteosarcoma cells. GS is an enzyme catalyzing the conversion of glutamate and ammonia to glutamine. Intracellular and extracellular glutamate levels may be important in cell signalling mediated by glutamate transporters and receptors which have recently been found in bone cells. The induction of GS protein by Dex was accompanied by an increase in mRNA level and enzyme activity. Dex induction of GS was also mediated by glucocorticoid receptors (GRs) because it was blocked by the GR antagonist RU-38486. In addition, Dex induction of GS expression was partially blocked by cyclohexamide indicating that it at least partly required new protein synthesis. GS induction by Dex was not associated with apoptosis as determined by Bax/Bcl-2 ratio and DNA staining. In addition to MG-63 cells, Dex induction of GS was also observed in human G-292 osteosarcoma cells as well as conditionally immortalized human preosteoblastic (HOB-03-C5) and mature osteoblastic (HOB-03-CE6) cells. However, in two other human osteosarcoma cell lines, SaOS-2 and U2-OS, GS expression was not affected by Dex. This observation may be explained by the lower levels of GR protein in these cells. In summary, this is the first report of the regulation of GS expression by glucocorticoids in bone cells. The role of GS in bone cell metabolism and glucocorticoid action on the skeleton is not yet known, but as a modulator of intracellular glutamate and glutamine levels, it may have an important role in these processes.

Apoptosis↗
PubMed2004

The association of bone metabolism with bone mineral density, serum sex hormone concentrations, and regular exercise in middle-aged men.

Physical activity is an important factor in attaining bone mass. Our aim was to investigate if low to moderate intensity exercise affects bone resorption [serum tartrate-resistant acid phosphatase (TRAP) 5b activity] and formation (serum osteocalcin concentration) in a randomized controlled exercise intervention trial in Finnish middle-aged men. In addition, the relations of these bone turnover markers with bone mineral density (BMD) and serum sex hormone concentrations [circulating testosterone (T), estradiol (E2), and sex hormone-binding globulin (SHBG) concentrations] were evaluated. Serum TRAP 5b activity and osteocalcin concentration were measured at randomization and after 1 and 4 years of the exercise intervention. BMDs of the lumbar spine (L2-L4), femoral neck, and total proximal femur were measured with a dual-energy X-ray absorptiometry (DXA). At randomization, TRAP 5b activity was strongly correlated with the osteocalcin concentration (Spearman r = 0.541, P < 0.0001). In addition, TRAP 5b activity was significantly correlated with proximal femur BMD values (r = -0.201, P = 0.018) and osteocalcin concentration with femoral neck and proximal femur BMD values (r = -0.187, P = 0.028; r = -0.240, P = 0.005, respectively). Serum E2, free E2, and free T concentrations were inversely correlated with both bone turnover markers. After 1 year of exercise intervention, TRAP 5b activity was significantly lower in the exercise than reference group (P = 0.006). However, after 4 years of exercise intervention, the difference was no longer statistically significant. There were no differences in the osteocalcin concentrations between the study groups during the intervention. Our results show a connection between serum TRAP 5b activity and osteocalcin concentration. Furthermore, our results suggest that low to moderate exercise intervention and serum sex hormone concentrations may induce changes in bone metabolism in middle-aged men. However, exercise-induced effects on bone metabolism should be confirmed in other randomized controlled exercise trials taking into account exercise intensity and dose-response issues.

Absorptiometry, Photon↗
PubMed2003

Aerobic exercise and bone mineral density in middle-aged finnish men: a controlled randomized trial with reference to androgen receptor, aromatase, and estrogen receptor alpha gene polymorphisms.

Our aim was to investigate associations of the polymorphic loci of androgen receptor (AR), aromatase CYP19, and estrogen receptor alpha (ERalpha) genes with bone mineral density (BMD) in a four-year controlled randomized exercise intervention trial in Finnish middle-aged men. Additionally, we studied whether the gene polymorphisms affect circulating testosterone (T), estradiol (E(2)), and sex hormone-binding globulin concentrations. The polymorphic CAG repeat of the AR gene, the TTTA repeat of the human aromatase gene, and the PvuII site of the ERalpha gene were analyzed. BMDs of the lumbar spine (L2-L4), femoral neck, and total proximal femur were measured with a dual-energy X-ray absorptiometry (DXA). In the exercise group, the subjects with the ERalpha gene PP or Pp genotypes showed an increase (+6.5 and +5.1%, respectively) in lumbar spine BMDs (P = 0.007; repeated measures ANOVA) during intervention, while there was no change in the subjects with the pp genotype. The long TTTA repeat (TTTA(9-12)) in aromatase gene was associated with greater height (P = 0.026) and lower BMI (P = 0.029) values than the short TTTA repeat (TTTA(6-8)). With regard to the AR gene, no statistically significant differences in bone properties were found between the genotypes. There were no significant associations of any analyzed polymorphic sites with the serum sex steroid hormone concentrations in the exercise or reference group. In conclusion, the Finnish middle-aged men with ERalpha PP or Pp genotypes appear to have increased BMD values in the lumbar spine. This increase may reflect a predisposition to age-related degenerative changes in the spine. In addition, the AR CAG repeat and aromatase TTTA repeat do not modify the effect of regular aerobic exercise on BMD.

Aromatase↗
PubMed2001

Genetic determinants of bone mineral content in premature infants.

Genetic determinants of bone mineral content in prematurely born children at 3 months and 9-11 years of age were studied. The findings suggest that multiple genes are involved in the regulation of site specific bone mass accumulation during childhood.

Absorptiometry, Photon↗
PubMed2000

Mechanism of action of superactive vitamin D analogs through regulated receptor degradation.

We and others have previously shown that selected vitamin D analogs potentiate the vitamin D receptor (VDR) mediated transcription much more efficiently than the natural hormone itself. Here we show that the transcriptionally active 20-epi analogs, namely KH 1060 and MC 1288, protect VDR against degradation more efficiently than calcitriol at 10(-10) M concentration (VDR t(1/2) > 48 h, 17 h, and 10 h, respectively). The conformationally epi-like analog EB 1089 did not significantly alter the half-life of VDR (10.3 h), but retained the VDR levels over longer periods of time than calcitriol. The transcriptionally weak analog GS 1558, on the other hand, enhanced VDR degradation even more than what was observed with the unliganded receptor (t(1/2) 4.5 h and 5 h, respectively). Inhibition of proteasome activity by the inhibitor MG-132 resulted in a marked increase in the VDR levels in cells treated with the vehicle or GS 1558 (2.5-fold and 2.7-fold, respectively), more than twice the levels observed in the presence of calcitriol or EB 1089 (1.2-fold and 1.1-fold, respectively). MG-132 treatment did not increase the VDR levels in cells treated with KH 1060 or MC 1288. The electrophoretic mobility shift assay (EMSA) with nuclear extracts from MG-132-treated cells revealed formation of a high-molecular-weight RXRbeta-VDR-VDRE complex, which also contained Sug1. In the presence of calcitriol, 34% of total VDR in its DNA binding state was present in this complex. The 20-epi analogs effectively prevented the formation of this complex, since, in this case, only 16% of total VDR was found in this complex. These results suggest that KH 1060 and MC 1288 induce a VDR conformation, which prevents binding of proteins mediating receptor degradation. As a result, the regulation of VDR degradation differs from that found with the calcitriol-VDR complex resulting in superactive transcriptional action of the analogs.

Calcitriol↗
PubMed2000

The protective effect of hormone-replacement therapy on fracture risk is modulated by estrogen receptor alpha genotype in early postmenopausal women.

Genetic factors regulate bone mineral density (BMD) and possibly development of osteoporosis. It has been suggested that estrogen receptor alpha (ERalpha) genotype is associated with BMD, but the association between ERalpha genotype, fracture risk, and postmenopausal hormone replacement therapy (HRT) has not been studied. Therefore, we evaluated whether ERalpha polymorphism is associated with fracture risk in a 5-year trial with HRT in a population-based, randomized group of 331 early postmenopausal women. The participants consisted of two treatment groups: the HRT group (n = 151) received a sequential combination of 2 mg of estradiol valerate (E2Val) and 1 mg of cyproterone acetate with or without vitamin D3, 100-300 IU + 93 mg calcium as lactate per day; and the non-HRT group (n = 180) received 93 mg of calcium alone or in combination with vitamin D3, 100-300 IU/day. All new symptomatic, radiographically defined fractures were recorded. Pvu II restriction fragment length polymorphism of the ERalpha was determined using polymerase chain reaction (PCR). In all, 28 women sustained 33 fractures during the approximately 5.1-year follow-up. In the HRT group, the ERalpha genotype (PP, Pp, and pp) was not significantly associated with fracture risk (p = 0.138; Cox proportional hazards model). When the genotype was dichotomized (PP + Pp vs. pp), the incidence of new fractures in the HRT group was significantly reduced in women with the P allele (p = 0.046) with the relative risk (HR) of 0.25 (95% CI, 0.07-0.98), in comparison with the non-P allele group. After adjustment for time since menopause and previous fracture, the association between the dichotomous genotype and fracture risk persisted with HR of 0.24 (95% CI, 0.06-0.95;p = 0.042). In the non-HRT group, the ERalpha genotype was not significantly associated with fracture risk. During HRT, women with the pp genotype have a greater fracture risk than those with the P allele. The results suggest that the pp genotype is a relatively hormone-insensitive genotype, and it appears that women with the P allele may benefit more from the protective effect of HRT on fracture risk than women with the pp genotype.

Androgen Antagonists↗
PubMed2000

Early postmenopausal bone loss is associated with PvuII estrogen receptor gene polymorphism in Finnish women: effect of hormone replacement therapy.

Genetic factors regulate bone mineral density (BMD) and possibly the development of osteoporosis. An association between estrogen receptor (ER) polymorphism, BMD, and postmenopausal hormone replacement therapy (HRT) has not been established. Therefore, we studied the influence of the ER genotype on BMD before and after a 5-year HRT in a placebo-controlled, population-based, randomized group of 322 early postmenopausal women. The participants were randomized into two treatment groups: the HRT group (n = 145) received a sequential combination of 2 mg estradiol valerate and 1 mg CPA with or without vitamin D3, 100-300 IU + 500 mg calcium lactate/day (equal to 93 mg Ca2+), and the non-HRT group (n = 177) received calcium lactate, 500 mg alone or in combination with vitamin D3, 100-300 IU/day. PvuII restriction fragment length polymorphism (RFLP) of the ERalpha was determined using polymerase chain reaction (PCR). BMDs of the lumbar spine (L2-4) and proximal femur were measured by using dual-energy X-ray absorptiometry (DXA). At the baseline, there were no significant differences in the lumbar or femoral neck BMDs between the three ER PvuII genotype groups (PP, Pp, pp). After 5 years, the BMD of the femoral neck remained unaltered and that of the lumbar spine increased by 1.7% in the HRT group, whereas both BMDs were decreased by 4-5% in the non-HRT group. The ER genotype did not modulate the femoral neck BMD change during the follow-up. In contrast, in the non-HRT-group the lumbar spine BMD decreased more in subjects with the ER genotypes PP (6.4%) and Pp (5.2%) than in subjects with the pp genotype (2.9%) (p = 0.002). In the HRT group, the relative changes of the lumbar spine BMD were similar in all three ER genotype groups. Thus without HRT, the pp genotype was associated with a smaller decrease in the lumbar spine BMD than the Pp and PP genotypes. Long-term HRT seemed to eliminate the ER genotype-related differences in the BMD. We conclude that subjects with the ER PvuII genotypes PP and Pp may have a greater risk of relatively fast bone loss after menopause than those with the pp genotype and that they may preferentially derive benefit from HRT.

Deoxyribonucleases, Type II Site-Specific↗
PubMed1998

Type I procollagen synthesis is regulated by steroids and related hormones in human osteosarcoma cells.

Change in the synthesis of type I collagen, the major extracellular matrix component of skin and bone, are associated with normal growth, tissue repair processes, and several pathological conditions. Expression of the COL 1A1 gene is regulated by transcriptional and post-transcriptional mechanisms. However, the hormonal regulation of type I collagen synthesis in human bone has not been well characterized. We have studied the influence of calcitriol, dexamethasone, retinoic acid, and estradiol on the COL 1A1 gene expression by determining the secretion of the C-terminal propeptide (PICP) and the levels of alpha 1(I) procollagen mRNA in cultured human MG-63 and SaOs-2 osteoblast-like osteosarcoma cells. Similar experiments were also performed with respect to expression of the nuclear proto-oncogenes, c-fos and c-jun, in MG-63 cells. In MG-63 cells, calcitriol stimulated the synthesis and secretion of PICP. The alpha 1(I) procollagen mRNA level was elevated with no effect on message stability, indicating a transcriptional mechanism of regulation. In contrast, dexamethasone treatment was accompanied by an accelerated rate of alpha 1(I) procollagen mRNA turnover, observed as decreased amounts of the message and the secreted PICP, implying a posttranscriptional regulation. Retinoic acid, in turn, decreased the levels of alpha 1(I) procollagen mRNA and secreted PICP by slowing down transcription of the COL1A1 gene without any effect on message stability. The ability of these hormones to regulate the alpha 1(I) transcripts was sensitive to puromycin treatment, suggesting an involvement of an induced mediator protein in the action of the hormones on the COL1A1 gene. Both dexamethasone and calcitriol rapidly but transiently increased the expression of the c-fos and c-jun proto-oncogenes. Neither proto-oncogene responded to retinoic acid treatment with significant changes in mRNA levels. Estradiol treatment was found to have no influence on type I procollagen synthesis. In SaOs-2 cells, which are not as well differentiated as the MG-63 cells, calcitriol and dexamethasone did not influence type I procollagen synthesis. Retinoic acid as well as estradiol reduced collagen gene expression in these cells. These findings suggest that hormonal effects on type I procollagen synthesis may depend on the maturational state of the osteoblastic cells that express different regulatory factors and receptors, resulting in, in each case, a finely adjusted rate of gene expression.

Administration, Topical↗
PubMed1996

Synthetic 20-epi analogs of calcitriol are potent inducers of target-gene activation in osteoblastic cells.

We have compared the actions of calcitriol and its three synthetic analogs, 20-epi-22-oxa-24a,26a,27a-trihomo-1 alpha,25-dihydroxyvitamin D3 (KH 1060), 1 alpha,24S-(OH)2-22-ene-26,27-cyclopropyl vitamin D3 (MC 903) and 20-epi-1 alpha,25-dihydroxyvitamin D3 (MC 1288), on the expression of two marker genes of differentiated osteoblasts, namely alkaline phosphatase and osteocalcin, using human MG-63 osteosarcoma cells. Calcitriol and the analogs had qualitatively similar stimulatory effects on target-gene activation. Quantitatively, MC 903 behaved in most experiments essentially as the parent compound calcitriol. In vitamin D receptor/DNA complex formation MC 903, however, was more potent than calcitriol. In contrast, the 20-epi analogs, KH 1060 and MC 1288, were much more potent even at lower concentrations, than calcitriol and MC 903 in stimulating alkaline phosphatase activity, osteocalcin mRNA synthesis and osteocalcin secretion. The stimulation occurred to a greater degree and for a longer period than with calcitriol. This effect was apparently mediated by stronger and longer lasting binding of the vitamin D receptor to the osteocalcin vitamin D responsive element by the 20-epi analogs. After a 6-h treatment and during subsequent culture without hormone, the effects of the 20-epi analogs were also stronger and lasted longer than those with calcitriol or MC 903. Collectively, at comparable and lower concentrations, the 20-epi analogs, KH 1060 and MC 1288, mediate much stronger and longer lasting stimulatory effects than calcitriol or its analog MC 903 on target-gene expression associated with the differentiated phenotype of the MG-63 human osteosarcoma cells.

Alkaline Phosphatase↗
PubMed1996

A novel vitamin D analog with two double bonds in its side chain. A potent inducer of osteoblastic cell differentiation.

EB 1089 (1 alpha,25-dihydroxy-22,24-diene-24,26,27-trihomovitamin D3) is a novel, synthetic analog of calcitriol, characterized by two extra double bonds in its side chain. It is less potent than calcitriol in its calcemic action, but is an order of magnitude more potent in its antiproliferative action. The aim of this study was to determine the ability of EB 1089 to induce the well-known biological effects of calcitriol in MG-63 human osteosarcoma cells (i.e. by inhibiting cell proliferation and by induction of differentiation). Both calcitriol and EB 1089 significantly decreased cell growth after 2 days in culture. At 5 days, however, Eb 1089 was more potent than the natural hormone in inhibiting the proliferation of MG-63 cells. Potent effects of EB 1089 on cell differentiation were also seen in the stimulation of alkaline phosphatase activity, cellular vitamin D receptor mRNA levels, and medium osteocalcin synthesis. EB 1089 was clearly more effective than calcitriol in stimulating alkaline phosphatase activity and osteocalcin synthesis. In gel shift assays, the binding of vitamin D receptor to the composite AP-1 plus vitamin-D responsive promoter region of the human osteocalcin gene after EB 1089 treatment was stronger and longer-lasting than after calcitriol treatment.

Antineoplastic Agents↗
PubMed1994

Steroid hormone modulation of vitamin D receptor levels in human MG-63 osteosarcoma cells.

The effects of steroid and thyroid hormones are mediated by intracellular hormone receptors. An important mechanism modulating target tissue responsiveness to hormones is homologous and heterologous regulation of the receptors. We have characterized the expression of steroid hormone receptors in human MG-63 osteosarcoma cells. The MG-63 cells express receptor mRNAs for glucocorticoids, estrogen, retinoic acid, and 1,25(OH)2D3. We found that only the vitamin D receptor (VDR) mRNA concentration was influenced by the hormones. The stability of the VDR message was identical in control, dexamethasone- and estradiol-treated cells. On the other hand, both 1,25(OH)2D3 and retinoic acid separately stabilized the VDR mRNA levels increasing the apparent half-life by 11 h and 6 h, respectively. The VDR protein levels, however, as measured by immunoprecipitation, increased only after the 1,25(OH)2D3 treatment.

Blotting, Northern↗
PubMed1992

Characterization of human 1,25-dihydroxyvitamin D3 receptor anti-peptide antibodies.

Rabbit and chicken antibodies were raised against two peptides synthesized according to the structure of human 1,25-dihydroxyvitamin D3 receptor (hVDR): rabbit alpha hVDR-103 against the N-terminal amino acids 5-18 and alpha hVDR-104 against the amino acids 172-186 in the hinge region and chicken alpha hVDR-cab11 against the amino acids 172-186, respectively. The specificity of the antibodies was tested by peptide saturation, SDS-PAGE immunoblotting, gel shift assay and sucrose gradient centrifugation. Immunoblotting of a soluble extract (cytosol) from osteosarcoma cell line MG-63 showed a single band with an M(r) of about 48,000 and human intestine cytosol a broad band (50-63,000) for both antibodies. The antibodies recognized activated (3.2S) hVDR by shifting the centrifugation sedimentation profile to 5-6S. The antibodies showed nuclear immunostaining of unoccupied VDR in human osteosarcoma cells MG-63, U2-Os and SaOs-2. The immunoreaction could be saturated with the corresponding synthetic peptide. In immunoblot alpha hVDR-103 reacted with human and rat VDR, whereas alpha hVDR-104 recognized human VDR only. Similarly in immunohistochemistry, alpha hVDR-103 showed staining with hVDR and rVDR, whereas alpha hVDR-104 reacted only with hVDR. All antibodies recognized the native hVDR as verified with sucrose gradient centrifugation or immunoprecipitation but only alpha hVDR-103 and alpha hVDR-cab11 in gel shift assay of hVDR associated with the vitamin D-responsive element of human osteocalcin gene promoter.

Amino Acid Sequence↗
PubMed1991

Homologous and heterologous regulation of 1,25-dihydroxyvitamin D-3 receptor mRNA levels in human osteosarcoma cells.

The heterologous regulation of hormone receptors is well described in the hormone receptor literature. We were interested in determining whether human 1,25-dihydroxyvitamin D-3 receptor (hVDR) and glucocorticoid receptor (GR), members of the steroid/thyroid hormone receptor family, are heterologously regulated by other steroids and related hormones. We used human osteosarcoma cells (MG-63) and measured hVDR and GR mRNA levels after androgen, estrogen, glucocorticoid, progesterone, thyroid hormone, vitamin A and vitamin D treatments. Each hormone, except androgen and progesterone, was capable of increasing hVDR mRNA levels like the natural ligand in human osteosarcoma cells. On the other hand, GR gene expression was not affected by these hormones. To study whether the cells responded to the 1,25(OH)2D3-treatment with changes in differentiation and proliferation, we also studied c-myc and c-fos gene expression. Both genes were only regulated by 1,25(OH)2D3. 1,25(OH)2D3 slightly increased the accumulation of c-fos mRNA within 4-12 h from the hormone addition, while the increase in c-myc mRNA appeared at 24 h.

Autoradiography↗
PubMed1991

Use of non-collagen markers in osteoporosis studies.

Clinical and research laboratories routinely measure various hormonal and nonhormonal parameters of calcium and phosphorus metabolism, and markers of bone turnover. Such measurements may help clinical decision-making relating to metabolic bone disease and osteoporosis. Molecular biological and cell-culture techniques are being used in basic biochemical research on bone-cell metabolism. Results may aid understanding of normal and abnormal regulation of the bone-cell metabolism, and thus provide further insights relating to the diagnosis and prevention of osteoporosis.

1-Carboxyglutamic Acid↗
PubMed1991

Hormonal regulation of vitamin D receptor levels and osteocalcin synthesis in human osteosarcoma cells.

1,25(OH)2D3 was found to regulate its own receptor levels via an increase in corresponding mRNA levels in human osteoblast-like osteosarcoma cells (MG-63). In addition, exposure of the cells for 24h to dexamethasone, estradiol, retinoic acid, or triiodothyronine resulted in a dose-dependent accumulation of hVDR mRNA. Combination of 1,25(OH)2D3 with any other hormone used in this study did not result in an additive increase in hVDR mRNA levels. Progesterone or dihydrotestosterone did not influence hVDR mRNA levels. Of the studied hormones, only 1,25(OH)2D3 was alone able to stimulate the synthesis and secretion of osteocalcin. Compared with 1,25(OH)2D3, the combination of 1,25(OH)2D3 and retinoic acid resulted an increased synthesis of osteocalcin. In contrast, the combination of 1,25(OH)2D3 with dexamethasone, estradiol, or triiodothyronine diminished the stimulatory effect of 1,25(OH)2D3. A complex interaction of several different hormone receptors seems to occur within the regulatory regions of hVDR and osteocalcin genes, or at the level of translation, resulting, in each case, a finely adjusted vitamin D receptor and osteocalcin expression.

Calcitriol↗
PubMed1991

Modulation of 1,25(OH)2D3-induced osteocalcin synthesis in human osteosarcoma cells by other steroidal hormones.

We have previously shown that osteocalcin synthesis is readily induced by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in MG-63 human osteosarcoma cells (Mahonen et al. (1990) Biochim. Biophys. Acta 1048, 30-37). In the present study, the regulation of osteocalcin synthesis by other hormones of the steroid-thyroid hormone family (retinoic acid, 17 beta-estradiol, triiodothyronine, and dexamethasone) was examined. We found that the other hormones alone had no effects on medium osteocalcin and osteocalcin mRNA concentrations by 96 h of treatment. Compared with 1,25(OH)2D3, however, the combination of 1,25(OH)2D3 with dexamethasone resulted in a greatly reduced medium osteocalcin concentration. Also estradiol and triiodothyronine diminished the stimulatory effect of 1,25(OH)2D3. In contrast, the combination of 1,25(OH)2D3 with retinoic acid resulted in an increased medium osteocalcin concentration. The inhibition of osteocalcin synthesis by dexamethasone and triiodothyronine was accompanied by decreased osteocalcin mRNA levels. Retinoic acid and estradiol, however, did not influence the 1,25(OH)2D3-induced osteocalcin mRNA levels. To examine the specificity of the hormonal effects, the activity of alkaline phosphatase was determined. Both baseline and 1,25(OH)2D3-stimulated alkaline phosphatase activity was found to be inhibited by all other hormones. These results suggest that the steroidal hormones specifically affect osteocalcin synthesis in osteoblastic bone cells, and that complex interactions occur at the level of transcription and/or translation resulting in each case in a finely adjusted rate of osteocalcin synthesis.

Alkaline Phosphatase↗