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PubMed1992

Abnormalities in circadian patterns of bone resorption and renal calcium conservation in type I osteoporosis.

We compared changes over 24 h in 15 postmenopausal normal women (mean [+/- SD] age, 64 +/- 7 yr) with those in 15 postmenopausal women with type I osteoporosis and vertebral fractures (mean age, 64 +/- 5 yr). The serum osteocalcin concentration, a sensitive index of bone formation, increased by about 5% at night in both groups. Urinary deoxypyridinoline excretion, a sensitive index of bone resorption, increased by 48% at night (P less than 0.01) in the normal women, whereas in the osteoporotic women it was 62% higher overall (P less than 0.05), and the increase persisted into the morning. At night, urinary fractional excretion of calcium decreased by 20% (P less than 0.001) in the normal women, but was unchanged in the osteoporotic women; this circadian pattern differed between groups (P less than 0.05). The serum ionized calcium concentration did not change at night in either group. There was a trend (P = 0.07) for blunting of the nocturnal increase in the serum intact PTH level in osteoporotic women. Thus, the nocturnal serum ionized calcium level is maintained by decreased urinary calcium excretion and increased bone resorption in postmenopausal normal women, but almost entirely by increased resorption in postmenopausal osteoporotic women. This greater dependence on bone resorption during the nocturnal fast may account in part for the greater bone loss in osteoporotic women.

Amino Acids↗
PubMed1998

Seasonal variation of biochemical indexes of bone turnover: results of a population-based study.

Biochemical markers of bone turnover have been shown to provide valuable information for the diagnosis and monitoring of metabolic bone disease. However, these dynamic indexes are influenced by a number of factors that need to be clearly identified to improve their clinical usefulness. To evaluate the contributions of anthropometric, life style, and environmental variables on bone turnover, biochemical markers of bone metabolism were determined in a population-based sample of 580 adults, aged 50-81 yr (297 men and 283 women). Subjects were recruited during 14 consecutive months within the framework of the European Vertebral Osteoporosis Study. Serum total and bone-specific alkaline phosphatase (S-BAP), serum C-terminal propeptide of type I collagen, and serum osteocalcin (S-OC) were measured as bone formation markers. Urinary total pyridinoline and deoxypyridinoline were included as bone resorption indexes. In females, serum levels of 25-hydroxyvitamin D3 were significantly higher (P < 0.01) in summer (May-September) than in winter (October-April), whereas no significant differences were found in males. In both sexes, no seasonal changes were seen in serum PTH. In males, serum total alkaline phosphatase (P < 0.01), S-BAP (P < 0.001), and S-OC (P < 0.05) were significantly higher in winter than in summer. During the same period, females had higher values of S-BAP (P < 0.05), S-OC (P < 0.01), and urinary pyridinoline and deoxypyridinoline (P < 0.001, respectively). Univariate analyses of the effects of life style habits on markers of bone metabolism revealed that in females, regular alcohol consumption and current smoking led to a suppression of markers of bone turnover, whereas in males, only alcohol intake was associated with such changes. In contrast, physical activity was associated with higher levels of bone formation markers and reduced levels of bone resorption indexes in both sexes. As shown by multivariate regression analyses, seasonal variations accounted for more of the variability in most biomarkers (up to 12%) than any of the other anthropometric or life style factors except age. This effect may be attributed to subclinical vitamin D deficiency during the winter period, which is common in countries of the northern hemisphere. We conclude that seasonal variation contributes significantly to the biological variability of bone turnover and needs consideration when interpreting the results of bone marker measurements.

Aged↗
PubMed2000

Responses of markers of bone and collagen turnover to exercise, growth hormone (GH) administration, and GH withdrawal in trained adult males.

To examine the interactions between acute exercise and GH on markers of bone and collagen turnover and to assess the potential for detecting GH abuse in athletes using these markers, we studied 17 aerobically trained males (age, 26.9+/-1.5 yr). Sequential studies of exercise, GH administration, and GH withdrawal were undertaken. A randomized, controlled study of rest vs. exercise showed that exercise did not change serum osteocalcin; other markers of formation increased transiently (each P<0.001): bone-specific alkaline phosphatase (+16.1%), carboxyterminal propeptide of type I procollagen (+14.1%), and procollagen III N-terminal extension peptide (+5.0%). The carboxyterminal cross-linked telopeptide of type I collagen, a bone resorption marker, increased 9.7% (P = 0.018) in response to exercise. A randomized, double blind, placebo-controlled, parallel study of recombinant human GH treatment (0.15 IU/kg x day) for 1 week increased serum osteocalcin (net increase preexercise, +/-10.0%; P = 0.017), carboxyterminal propeptide of type I procollagen (+17.6%; P = 0.002), procollagen III N-terminal extension peptide (+48.4%; P = 0.001), and carboxyterminal cross-linked telopeptide of type I collagen (53.3%; P = 0.009). Disappearance half-times after cessation of recombinant human GH for pre- and postexercise markers ranged from 248-770 h. We conclude 1) endurance exercise transiently activates bone and collagen turnover; 2) brief GH administration results in similar but quantitatively greater augmentation; and 3) these data will assist in designing a GH detection strategy.

Adolescent↗
PubMed2000

Insulin-like growth factor I (IGF-I) replacement during growth hormone receptor antagonism normalizes serum IGF-binding protein-3 and markers of bone formation in ovariectomized rhesus monkeys.

Previous work from this laboratory has shown that the constant sc infusion of insulin-like growth factor I (IGF-I) to normal pituitary monkeys results in a sustained elevation in circulating concentrations of IGF-binding protein-3 (IGFBP-3), whereas the acute administration of IGF-I to monkeys pretreated with a GH receptor antagonist produces a brief, but significant, elevation in serum IGFBP-3. The present study tested the hypothesis that the constant infusion of IGF-I would normalize serum concentrations of IGFBP-3 in females treated with the GH receptor antagonist. To assess the biological significance of these effects, serum levels of the acid-labile subunit (ALS) and biomarkers for bone formation, osteocalcin, and collagen type I C-terminal propeptide, were also examined. Five female rhesus monkeys were studied over 21 consecutive days involving 7 days of baseline, 7 days of treatment with the GH receptor antagonist (1.0 mg/kg-week, sc), and 7 days of treatment with the GH receptor antagonist supplemented with IGF-I (120 microg/kg x day, sc infusion with osmotic minipump). Within 48 h of the initiation of treatment with the GH receptor antagonist, serum IGF-I and IGFBP-3 were decreased by 40% and 18% from baseline, respectively, and levels continued to decline through the remainder of treatment. However, within 48 h of the initiation of IGF-I administration during GH receptor antagonist treatment, both serum IGF-I and IGFBP-3 were elevated and normalized to baseline values. Serum concentrations of ALS were also decreased by GH antagonism, but levels increased in some (n = 2), but not all, subjects upon administration of IGF-I. Size exclusion ultrafiltration indicated that the amount of IGF-I found in the high molecular mass complex (>100 kDa) decreased significantly during GH antagonism, but was similar during the baseline and IGF-I infusion phases. Finally, treatment with the GH receptor antagonist also significantly reduced serum levels of osteocalcin and collagen type I C-terminal propeptide, an effect reversed by the addition of IGF-I. These data support the hypothesis that IGF-I increases serum concentrations of IGFBP-3 when endogenous GH action is compromised and that such treatment produces biologically active IGF-I, as evidenced by normalization of biomarkers for bone formation. These results indicate that IGF-I administration during GH receptor antagonism restores circulating levels of IGFBP-3 and the amount of IGF-I found in the high molecular mass complex to levels observed during baseline conditions. It remains to be determined whether IGF-I directly affects hepatic synthesis and secretion of IGFBP-3 and what role IGF-I has in the direct regulation of ALS in the monkey.

Animals↗
PubMed2001

Milk basic protein promotes bone formation and suppresses bone resorption in healthy adult men.

Milk contains several components effective for bone health. In the previous in vitro and in vivo studies, we have shown that milk whey protein, especially its basic protein fraction (milk basic protein [MBP]), promoted bone formation and suppressed bone resorption. This present study examines the effect of MBP on the biochemical markers of bone metabolism in healthy adult men. Experimental beverages containing MBP (300 mg of MBP a day) were given to 30 normal healthy adult men for 16 days. The serum osteocalcin concentration had increased significantly after 16 days of ingesting the experimental beverage containing MBP. Urinary cross-linked N-teleopeptides of type-I collagen (NTx) excretion had decreased significantly after 16 days of ingesting MBP. The urinary NTx excretion was related to the serum osteocalcin concentration after 16 days of ingestion. These results suggest that MBP promoted bone formation and suppressed bone resorption, while maintaining the balance of bone remodeling.

Adult↗
PubMed2004

Overview on the application of transcription profiling using selected nephrotoxicants for toxicology assessment.

Microarrays allow for the simultaneous measurement of changes in the levels of thousands of messenger RNAs within a single experiment. As such, the potential for the application of transcription profiling to preclinical safety assessment and mechanism-based risk assessment is profound. However, several practical and technical challenges remain. Among these are nomenclature issues, platform-specific data formats, and the lack of uniform analysis methods and tools. Experiments were designed to address biological, technical, and methodological variability, to evaluate different approaches to data analysis, and to understand the application of the technology to other profiling methodologies and to mechanism-based risk assessment. These goals were addressed using experimental information derived from analysis of the biological response to three mechanistically distinct nephrotoxins: cisplatin, gentamicin, and puromycin aminonucleoside. In spite of the technical challenges, the transcription profiling data yielded mechanistically and topographically valuable information. The analyses detailed in the articles from the Nephrotoxicity Working Group of the International Life Sciences Institute Health and Environmental Sciences Institute suggest at least equal sensitivity of microarray technology compared to traditional end points. Additionally, microarray analysis of these prototypical nephrotoxicants provided an opportunity for the development of candidate bridging biomarkers of nephrotoxicity. The potential future extension of these applications for risk assessment is also discussed.

Animals↗
PubMed2004

Regulation of human skeletal stem cells differentiation by Dlk1/Pref-1.

UNLABELLED: Dlk-1/Pref-1 was identified as a novel regulator of human skeletal stem cell differentiation. Dlk1/Pref-1 is expressed in bone and cultured osteoblasts, and its constitutive overexpression led to inhibition of osteoblast and adipocyte differentiation of human marrow stromal cells. INTRODUCTION: Molecular control of human mesenchymal stem cell (hMSC) differentiation into osteoblasts and adipocytes is not known. In this study, we examined the role of delta-like 1/preadipocyte factor-1 (Dlk1/Pref-1) in regulating the differentiation of hMSCs. MATERIALS AND METHODS: As a model for hMSCs, we have stably transduced telomerase-immortalized hMSC (hMSC-TERT) with the full length of human Dlk1/Pref-1 cDNA and tested its effect on hMSC growth and differentiation into osteoblasts or adipocytes as assessed by cytochemical staining, FACS analysis, and real time PCR. Ex vivo calvaria organ cultures assay was used to confirm the in vitro effect of Dlk/Pref-1 on bone formation. RESULTS: Dlk1/Pref-1 was found to be expressed in fetal and adult bone, hMSCs, and some osteoblastic cell lines. A retroviral vector containing the human Dlk1/Pref-1 cDNA was used to create a cell line (hMSC-dlk1) expressing high levels of Dlk1/Pref-1 protein. Overexpression of Dlk1/Pref-1 did not affect the proliferation rate of hMSC, but the ability to form mature adipocytes, mineralized matrix in vitro, and new bone formation in neonatal murine calvariae organ cultures was reduced. These effects were associated with inhibition of gene expression markers of late stages of adipocyte (adipocyte fatty acid-binding protein [aP2], peroxisome proliferator-activated receptor-gamma2 [PPARgamma2], and adiponectin [APM1]) and osteoblast differentiation (alkaline phosphatase [ALP], collagen type I [Col1], and osteocalcin [OC]). Lineage commitment markers for adipocytes (adipocyte determination and differentiation factor -1 [ADD1]) and osteoblasts (core binding factor/runt-related binding factor 2 [Cbfa1/Runx2]) were not affected. CONCLUSION: During hMSC differentiation, Dlk1/Pref-1 maintains the size of the bipotential progenitor cell pool by inhibiting the formation of mature osteoblasts and adipocytes.

Adipocytes↗
PubMed1997

Evidence for increased bone formation following a brief endurance-type training intervention in adolescent males.

The effect of exercise training, particularly relatively brief periods, on bone turnover markers in adolescents has been poorly studied. Thirty-eight healthy males (16+/-0.7 years) participated in a 5-week summer school program in which 20 subjects were randomly assigned to a training group consisting of 2 h/day, 5 days/week of endurance exercise, and 18 subjects were assigned to a control group. Bone formation was assessed by measurements of circulating osteocalcin, bone-specific alkaline phosphatase (BSAP), and the C-terminal procollagen peptide (PICP). Bone resorption was assessed by urinary levels of free deoxypyridinoline cross-links (dPYR) and the C-(CTX) and N-terminal (NTX) telopeptide cross-links. Prior to training, there was a weak positive correlation between fitness and PICP (r = 0.27, p < 0.05), but no correlations were observed between fitness and either the other markers of bone formation or bone resorption. Training led to a significant increase in (1) osteocalcin (15+/-4%, p < 0.03), (2) BSAP (21+/-6%, p < 0.02), and (3) PICP (30+/-11%, p < 0.03) and to a significant decrease in NTX (-21 +/- 3%, p < 0.05). These bone turnover markers did not change in the control subjects (osteocalcin, 0+/-4%; BSAP, 2+/-4%; PICP, -4 +/- 6%; NTX, -6 +/- 4%). There was no change in urinary dPYR and CTX in either control or trained subjects. Fitness is only weakly, if at all, correlated with bone formation, but a relatively brief period of endurance training leads to a substantial increase in bone formation markers in adolescent males. School-based, short-term exercise training programs could play a role in enhancing bone formation in adolescents.

Adolescent↗
PubMed1998

Comparison of markers of bone formation and resorption in prostate cancer patients to predict bone metastasis.

We investigated the usefulness of two biochemical markers of bone formation (PICP, the carboxy-terminal propeptide of type I procollagen, and bone ALP, bone-derived alkaline phosphatase) and a marker of bone resorption (ICTP, the carboxy-terminal telopeptide of type I collagen), to determine whether the presence of bone metastasis in prostate cancer could be evaluated and the extent of bone metastasis could be stratified by the serum levels of these markers, compared to total alkaline phosphatase (T-ALP) and prostate-specific antigen (PSA). The serum levels of PICP, bone ALP, ICTP, T-ALP and PSA were significantly higher in patients with both prostate cancer and bone metastasis (n=49) than in patients with benign prostatic hyperplasia (n=35) and patients with prostate cancer without bone metastasis (n=70). The superiority of a marker in the rate of detection of bone metastasis was evaluated with receiver operating characteristic curves. The serum marker levels were compared as a function of metastatic burden in bone (i.e., the extent of disease, EOD grade). We found that bone ALP is the most suitable marker for evaluating bone metastasis, especially for stratifying the degree of bone metastasis. Both PICP and ICTP were useful in this respect, but rather inferior to bone ALP. T-ALP had the lowest ability for detecting bone metastasis, but its correlation with the EOD grade was excellent, second to that of bone ALP. PSA showed limited reliability for stratifying the extent of bone metastasis.

Aged↗
PubMedDate not supplied

Effects of 12 months rhGH treatment on bone and collagen turnover in children with constitutional growth delay.

Serum bone Gla protein (BGP), marker of osteoblast function, serum carboxyterminal cross-linked telopeptide of type I collagen (ICTP) and urinary free deoxypyridinoline (DPD), markers of bone resorption, and the aminoterminal propeptide of type III procollagen (PIIINP), marker of type III collagen turnover, were determined in eight prepubertal children (8 males, age range 7-9.6 yr, Tanner stage I) with constitutional growth delay (CGD), before and after 6-12 months of treatment with rhGH (Saizen, Serono, 0.6 IU/kg/week, s.c.). Serum BGP (mean+/-SD: 15.4+/-1.7 ng/ml), ICTP (9.4+/-1.6 ng/ml) and urinary DPD/creatinine (11.3+/-1.7 nmol/mmol) levels were significantly lower (p<0.02, p<0.0001 and p<0.02, respectively) in children with CGD than in healthy age-matched controls (BGP: 18.9+/-3.6 ng/ml, ICTP: 14.3+/-2.6 ng/ml, DPD: 20.7+/-10.0 nmol/mmol), while PIIINP levels of patients were similar to those recorded in controls (6.3+/-0.7 vs 6.7+/-2.3 ng/ml, respectively). Serum BGP, urinary free DPD/creatinine and PIIINP levels significantly increased after 6 (BGP: 20.9+/-2.1 ng/ml, p<0.0001; DPD/creatinine: 16.3+/-3.6 nmol/mmol, p<0.001; PIIINP: 8.1+/-1.6 ng/ml, p<0.005) and 12 months (BGP: 19.2+/-2.0 ng/ml, p<0.0001; DPD/creatinine: 19.7+/-5.1 nmol/mmol, p<0.001; PIIINP: 8.8+/-1.9 ng/ml, p<0.002) of GH treatment. Serum ICTP levels did not significantly change after 6 months (10.6+/-2.1 ng/ml), while a significant increase (p<0.002) was evident after 12 months of therapy (13.6+/-1.3 ng/ml). Our study shows that BGP, ICTP and DPD/creatinine levels are significantly reduced in children with CGD, thus indicating the presence of low bone turnover in this form of short stature. Since GH treatment is able to reactivate bone remodeling and increase collagen synthesis, it is tempting to speculate that a partial GH-IGF-I defect (i.e. locally at bone level) might be one of the factors involved in determining the biochemical alterations of bone metabolism found in this clinical condition.

Biomarkers↗
PubMed2005

Evaluation of the activity of tartrate-resistant acid phosphatase isoform 5b in normal Chinese children--a novel marker for bone growth.

BACKGROUND: Most parents are very concerned about the height of their children. Biochemical markers of bone formation and resorption may provide useful clinical predictors for bone growth. Tartrate-resistant acid phosphatase 5b (TRAcP 5b) has been advocated as a biomarker of osteoclast activity and bone resorption. However, the TRAcP 5b levels of children at different ages are still unknown. It is necessary to accumulate and analyze the data for healthy children at different ages. OBJECTIVES: We use an improved immunoassay for bone TRAcP 5b to examine sera from children to see whether it is a significant marker of bone growth. METHODS: Serum, including cord blood, was collected from 404 normal Chinese children (age range 0-17 years; 225 male, 179 female). The venous blood was withdrawn from the peripheral vein and stored at 4 degrees C before centrifugation for serum collection. All sera were stored at -70 degrees C and thawed at 37 degrees C immediately before TRAcP 5b levels were measured. Bone-specific alkaline phosphatase (BAP) was also used for comparison with TRAcP 5b levels at different ages. RESULTS: TRAcP 5b levels were extremely high in infants of both genders, gradually decreasing with age (p <0.001). A second peak in TRAcP 5b values occurred at 12-13 and 10-11 years in males and females, respectively (p <0.001). Age alone, as well as age-related changes between the male and female groups, were independent predictors of TRAcP 5b levels (p <0.001). There was no significant between-gender difference in serum TRAcP 5b levels for any age group (p = 0.682). BAP values did not show a significant second peak in females. Age and gender alone, as well as the age-related changes between male and female groups, were independent predictors of BAP values (p <0.001). CONCLUSION: Preliminary results were established for serum TRAcP 5b and BAP values of normal Chinese children of different ages. Elevated serum TRAcP 5b values were observed during infancy and puberty for both genders. The pattern of this age-related change in serum TRAcP 5b levels is similar to the shape of the standard height velocity curve for healthy children. Values of BAP were less specific than TRAcP 5b. These data may prove valuable as a normal reference in future research about bone markers.

Acid Phosphatase↗
PubMed1995

Collagen metabolism in two types of autosomal dominant osteopetrosis during stimulation with thyroid hormones.

In order to investigate collagen metabolism in two different types of autosomal dominant osteopetrosis (ADO), eight patients with type I (aged 23-61 years, mean 40.4 years) and nine patients with type II ADO (aged 20-49 years, mean 32.8 years) were compared with ten normal controls (aged 22-54 years, mean 35.4 years). The subjects were treated with 100 micrograms of triiodothyronine (T3) daily for 7 days and followed for a total of 4 weeks. Serum T3 increased in all subjects and a corresponding suppression of thyroid-stimulating hormone (TSH) was observed. Serum carboxy-terminal propeptide of type I collagen (S-PICP) in the control and type I groups showed no difference at baseline, whereas type II was lower than controls (p < 0.01). No significant alterations following stimulation were observed in any of the groups. Serum BGP (osteocalcin) values in the two patient groups were insignificantly lower than controls both at baseline and throughout the study. Following stimulation, a significant response was seen in the three groups (p < 0.001). The increases during the treatment period (delta values) for controls, type I and type II were 47.6% (p < 0.01), 51.7% (p = 0.05) and 34.8% (NS), respectively, with no difference between the groups. Serum bone-specific alkaline phosphatase (S-ALP) was not different between the groups and no alterations were observed in relation to treatment. The serum N-terminal propeptide of type III collagen (S-PIIINP) showed no difference at baseline between type I and controls but was significantly higher (p < 0.003) in type II than in the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1998

Biochemical markers of bone metabolism in benign human osteopetrosis: a study of two types at baseline and during stimulation with triiodothyronine.

Biochemical markers of bone remodelling were used to evaluate bone turnover in two types of autosomal dominant osteopetrosis (ADO) at baseline and during stimulation with triiodothyronine (T3). Eight patients with Type I (aged 23-61 years, mean 40.4 years) and nine patients with Type II ADO (aged 20-49 years, mean 32.8 years) were compared with 10 normal controls (aged 22-54 years, mean 35.4 years). The participants were treated with 100 microg T3 daily for 7 days and followed for a total of 16 weeks. Serum concentrations of T3 increased and corresponding suppression of TSH was observed in all participants. Both formative and resorptive bone markers were normal at baseline. After stimulation with T3, a significant increase was seen in all groups for the formative markers used. Secondary increments were observed at the end of the observation period for all groups, indicating activation of bone remodelling. A variety of resorptive markers was assessed, but no differences between patients and controls were seen. After stimulation, highly significant responses were found in all parameters in all groups, in accordance with stimulation of existing resorptive cells. However, no secondary increments were seen at the end of the observation period. A more pronounced response was found in crosslinks-related assays. The study demonstrates that it is possible to stimulate bone resorptive and formative cells with thyroid hormones in both types of ADO. Moreover, it indicates that the remodelling process is activated by a short course of T3 treatment.

Adult↗
PubMed2005

Seasonality of growth response to GH therapy in prepubertal children with idiopathic growth hormone deficiency.

OBJECTIVE: Longitudinal growth of children exhibits seasonal variation. In both healthy children and in children with growth hormone (GH) deficiency (GHD) receiving GH therapy, growth rate is maximal during spring and summer. In the present study, we analyzed the growth response to GH therapy in children with GHD as a function of the season when therapy was started. SUBJECTS AND METHODS: Anthropometric measurements and biochemical analyses of GH secretion status and bone formation were longitudinally assessed in a cohort of 52 prepubertal children with GHD (14 girls, mean age 7.6 years) who were treated with a fixed dose of GH (0.025 mg/kg/day). RESULTS: Auxological assessments over the 2-year observation period revealed a significantly better growth response to GH therapy in children who started therapy between the spring and summer (group 1) compared with children who started in the autumn or winter (group 2). The difference was largest in the initial 3-month treatment period (35%; P<0.01). The initial better gain in height of group 1 was sustained during the study period. Baseline peak GH levels during stimulation tests and insuin-like growth factor-I levels did not differ between the two groups. However, group 1 had significantly higher bone resorption and formation markers, either at the start or shortly after initiation of GH treatment. This suggests that children with GHD have higher bone turnover during spring and early summer, irrespective of GH therapy. CONCLUSIONS: In summary, this study suggests that the season of GH initiation is a determinant of the initial growth response to GH replacement in prepubertal children with GHD.

Biomarkers↗
PubMed2004

Large-scale proteomic analysis of membrane proteins.

Proteomic analysis of membrane proteins is a promising approach for the identification of novel drug targets and/or disease biomarkers. Despite notable technological developments, obstacles related to extraction and solublization of membrane proteins are encountered. A critical discussion of the different preparative methods of membrane proteins is offered in relation to downstream proteomic applications, mainly gel-based analyses and mass spectrometry. Frequently, unknown proteins are identified by high-throughput profiling of membrane proteins. In search for novel membrane proteins, analysis of protein sequences using computational tools is performed to predict the presence of transmembrane domains. This review also presents these bioinformatic tools with the human proteome as a case study. Along with technological innovations, advancements in the areas of sample preparation and computational prediction of membrane proteins will lead to exciting discoveries.

Mass Spectrometry↗
PubMed2001

Relative potencies of 1,25-(OH)(2)D(3) and 19-Nor-1,25-(OH)(2)D(2) on inducing differentiation and markers of bone formation in MG-63 cells.

19-Nor-1,25-(OH)(2)D(2), an analog of 1,25-(OH)(2)D(3), is used to treat secondary hyperparathyroidism because it suppresses parathyroid hormone synthesis and secretion with lower calcemic and phosphatemic activities. 19-Nor-1,25-(OH)(2)D(2) is approximately 10 times less active than 1,25-(OH)(2)D(3) in promoting bone resorption, which accounts in part for the low potency of this analog in increasing serum calcium and phosphorus. Concern that 19-nor-1,25-(OH)(2)D(2) also could be less potent than 1,25-(OH)(2)D(3) on bone formation led to a comparison of the potency of both compounds on osteoblasts. In the human osteoblast-like cell line MG-63, 1,25-(OH)(2)D(3) and 19-nor-1,25-(OH)(2)D(2) had a similar potency in upregulating vitamin D receptor content and suppressing proliferation. Both sterols caused a similar reduction in DNA content and proliferating cell nuclear antigen protein expression. Time-course and dose-response studies on 1,25-(OH)(2)D(3) and 19-nor-1,25-(OH)(2)D(2) induction of the marker of bone formation, osteocalcin, showed overlapping curves. The effects on alkaline phosphatase (ALP) activity also were studied in MG-63 cells that had been co-treated with either sterol and transforming growth factor-beta, an enhancer of 1,25-(OH)(2)D(3)-induced ALP activity in this cell line. Transforming growth factor-beta alone had no effect, whereas 1,25-(OH)(2)D(3) and 19-nor-1,25-(OH)(2)D(2) increased ALP activity similarly. These studies demonstrate that 19-nor-1,25-(OH)(2)D(2) has the same potency as 1,25-(OH)(2)D(3) not only in inducing vitamin D receptor content, osteocalcin levels, and ALP activity but also in controlling osteoblastic growth. Therefore, it is unlikely that 19-nor-1,25-(OH)(2)D(2) would have deleterious effects on bone remodeling.

Alkaline Phosphatase↗