Vitamin D action and regulation in bone cells

It is well known that the biologically most active metabolite of vitamin D, I ,25-(0H)2DJ, is an essential hormone in the regulation of calcium homeostasis. Furthermore, evidence has accumulated to suggest that I ,25-(0H)2D3 regulates bone metabolism not only indirectly via its effect on intestinal absorption of calcium and phosphorus, but also directly through actions on bone remodelling cells and their progenitors. The aim of the present thesis has been to contribute to a better understanding of the effects of I,25-(0H)2D3 on the osteoblastic population and to investigate the cellular mechanisms in.volved in the regulation of the biological response to the hormon

Osteoporosis in the Netherlands; A burden of illness study commissioned by Merck Sharp & Dohme

This report provides an overview of the available quantitative information about osteoporosis in the Netherlands, and of the costs associated with it. We present information relevant for this country, making as few assumptions as possible. Although the main subject is osteoporosis, the focus in this report is on fractures, as these are the most relevant outcome events of this condition. Data were collected from publicly available data sources and from international literature and information is mostly about the year 1993. The reader finds detailed information about the occurrence of osteoporosis and fractures, the utilization of health care, mortality, and the costs in the results section of this report. In the conclusions, we present a synthesis of the most important findings. Osteoporosis is, by consensus, defined as a systemic skeletal disease, characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. There is an important age-related decrease in bone mass and bone strength. Osteoporosis is primarily described in post-menopausal women but men are not free from it; they also reach high fracture incidence rates at an older age. Combined with the longer survival of women, this leads to the observation that most osteoporotic fractures are encountered in females. Osteoporosis and fractures are a major source of illness and healthcare costs in the Netherlands, both today as in the foreseeable future. Especially the most serious consequence, hip fracture, is frequent and the incidence is increasing. The total number of hip fractures will inevitable rise if no serious prevention efforts are undertaken. For the prevention of osteoporotic fractures it is important to know who are at risk as well as which preventive strategy is effective for the different risk categories. The parameter that is most commonly used nowadays to determine fracture risk is bone mineral density (BMD), but also other factors are important contributors to the fracture risk, namely the previously mentioned bone quality and the propensity to fall. Prevention only focussed on bone mineral density will thus do nothing to prevent the hip fractures caused by the above mentioned factors. An additional effect of therapy on bone quality can be important and the intervention should certainly not have adverse effects on bone quality. Reducing the frequency and severity of falls, and the use of external protective devices, together with physical exercise and other lifestyle interventions, have been looked at as additional intervention possibilities. Patients with a hip fracture more often have concomitant illnesses and a poor general condition. This condition in itself can increase the risk of falling and the perioperative risk. This situation can also impair the rehabilitation after treatment and hamper mobilization. Osteoporosis and fractures are found to be an important cause of health care consumption. Hip fractures lead to long hospita

Vitamin D: A modulator of cell proliferation and differentiation

Abstract 1,25-Dihydroxyvitamin D3, [1,25(OH)2D3], the biologically most active metabolite of vitamin D3, is involved in the regulation of calcium homeostasis and bone metabolism. Recently, receptors for 1,25(OH)2D3 have also been shown in cells and tissues not directly related to calcium homeostasis. Experimental data obtained with leukemic and cancer cell lines, both in vitro and in vivo, showed the effects of 1,25(OH)2D3 on cell differentiation and proliferation. However, high doses of the sterol have to be used to observe these effects. Additional studies are needed to establish whether 1,25(OH)2D3 or suitable analogues have a therapeutic potential in malignant diseases without unacceptable toxicity like the development of hypercalcemia

Serum insulin-like growth factor binding protein-2 levels as an indicator of functional ability in elderly men

BACKGROUND: In a cross-sectional study in 403 healthy, independently living elderly men (mean age 78 years), we determined which are the main physiological determinants of functional ability in the elderly, and which components of the somatotropic system contribute to the maintenance of functional ability. METHODS: Functional ability was assessed by the number of problems in activities of daily living and by a measure of physical performance. Other physical characteristics included leg extensor strength, bone mineral density of total body and proximal femur, and body composition, including lean mass and fat mass. Serum insulin-like growth factor (IGF)-I and its binding proteins (IGFBP) -1, -2 and -3 concentrations were all measured by RIA. RESULTS: Muscle strength was related to a lower degree of disability. Further, it was positively related to physical performance and bone mineral density (all P<0.001). Fat mass influenced activities of daily living and physical performance negatively and bone mineral density positively (all P<0.001). Serum concentrations of IGF-I and IGFBP-3 were not related to any of the physical characteristics. High serum IGFBP-2 concentrations were related to a higher degree of disability (P<0.001), a lower physical performance (P=0.006), muscle strength (P=0.002), bone mineral density of proximal femur (P=0.007), lean mass and fat mass (both P<0.001). Serum insulin and IGFBP-1 concentrations were independently, positively related to lean mass (P=0.003) and fat mass (P<0.001). CONCLUSIONS: In independently living elderly men, functional ability appears to be determined by muscle strength (positive) and fat mass (negative). Low serum IGFBP-2 concentrations are a powerful indicator for overall good physical functional status, probably inversely reflecting the integrated sum of nutrition and the biological effects of growth hormone, IGF-I and insulin

Genetics and biology of vitamin D receptor polymorphisms

The vitamin D endocrine system is involved in a wide variety of biological processes including bone metabolism, modulation of the immune response, and regulation of cell proliferation and differentiation. Variations in this endocrine system have, thus, been linked to several common diseases, including osteoarthritis (OA), diabetes, cancer, cardiovascular disease, and tuberculosis. Evidence to support this pleiotropic character of vitamin D has included epidemiological studies on circulating vitamin D hormone levels, but also genetic epidemiological studies. Genetic studies provide excellent opportunities to link molecular insights with epidemiological data and have therefore gained much interest. DNA sequence variations, which occur frequently i

Modulation by epidermal growth factor of the basal 1,25(OH)2D3 receptor level and the heterologous up-regulation of the 1,25(OH)2D3 receptor in clonal osteoblast-like cells

The effects of epidermal growth factor (EGF) on basal 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) receptor level and on parathyroid hormone (PTH)-induced 1,25-(OH)2D3 (OH)2D3 receptor up-regulation were studied in the phenotypically osteoblastic cell line UMR 106. EGF in concentrations exceeding 0.1 ng/ml reduced the number of 1,25(OH)2D3 binding sites without changing the binding affinity. Maximal reduction was 30% at about 1 ng/ml. This reduction was independent of a change in cAMP content. EGF dose-dependently attenuated both PTH-induced 1,25(OH)2D3 receptor up-regulation and PTH-stimulated cAMP production without and effect on the ED50 of the PTH effects. For both PTH responses the IC50 and the maximal effective dose were similar, 0.1 ng/ml an 1 ng/ml EGF, respectively. Reduction was first seen at 0.01 ng/ml EGF. At this concentration. EGF reduced PTH-stimulated 1,25-(OH)2D3 receptor binding without an inhibition of the cAMP response. Time-course studies with 1 ng/ml EGF revealed that at 2 h preincubation EGF reduced the heterologous up regulation by PTH, and maximal inhibition was seen after 4 h. In contrast, PTH-stimulated cAMP production was just significantly inhibited only after 6 h, with 60% inhibition after 24 h preincubation. The effects of prostaglandin E2 and forskolin on both 1,25(OH)2D3 binding and cAMP production were inhibited in a similar fashion. On the other hand, dibutyryl cAMP- and 3-isobutyl-1-methylxanthinestimulated 1,25(OH)2D3 binding were not affected by EGF. Taken together, our results demonstrate that EGF reduces both the basal number of 1,25(OH)2D3 binding sites and the heterologous up-regulation of the 1,25(OH)2D3 receptor. The current data suggest that EGF reduces heterologous upregulation of the 1,25(OH)2D3 receptor independent of as well as dependent on the cAMP messenger system. The EGF effect is not primarily located at the PTH receptor, at cAMP phosphodiesterase, or at protein kinase A level

Evidence for coordinated regulation of osteoblast function by 1,25-dihydroxyvitamin D3 and parathyroid hormone

AbstractFrom several animal studies and clinical observations it became evident that at target tissue level 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and parathyroid hormone (PTH) must act in an interrelated manner. In the present study we examined the interaction between 1,25-(OH)2D3 and PTH in the target cell of these hormones in bone, the osteoblast. In addition we studied the role of PTH-activated signal pathways. The three osteoblastic cell lines UMR 106, ROS 172.8 and MG-63 were used as model systems. In UMR 106 cells 1,25-(OH)2D3 and PTH caused a synergistic up-regulation of the vitamin D receptor (VDR) which was accompanied by a synergistic induction of VDR mRNA expression whereas in both ROS 172.8 and MG-63 cells no interaction was observed. In UMR 106 cells the effect of PTH on homologous up-regulation of VDR could be mimicked by the cAMP agonist forskolin and by dibutyrylic-CAMP. Phorbol ester activation of protein kinase C reduced basal as well as 1,25-(OH)2D3-induced up-regulation of VDR. 1,25-(OH)2D3 induced 24-hydroxylase activity in UMR 106 and MG 63 cells and, in contrast to VDR regulation, in both cell lines PTH and 1,25-(OH)2D3 synergistically induce 24-hydroxylase activity. Similar to VDR regulation the effect of PTH was mimicked by activation of cAMP production whereas protein kinase C activation reduced the induction by 1,25-(OH)2D3 Finally, we examined the interaction with respect to osteocalcin synthesis. In ROS 172.8 and MG-63 cells 1,25-(OH)2D3 stimulated osteocalcin production. In ROS 172.8 cells PTH as well as stimulation of cAMP production by forskolin enhanced 1,25-(OH)2D3-induced osteocalcin production whereas, as we have shown previously, activation of protein kinase C does not change 1,25-(OH)2D3- stimulated osteocalcin production. In MG-63 cells neither PTH nor forskolin significantly changed 1,25-(OH)2D3 induction of osteocalcin synthesis. From the present study it can be concluded that indeed at target cell level 1,25-(OH)2D3 and PTH act in a coordinated manner. On basis of the potentiation of 1,25-(OH)2D3 action by PTH in osteoblasts together with the previously reported inhibition of PTH-stimulated cAMP production by 1,25-(OH)2D3 we postulate a negative feedback-loop at target cell level. The activation of the cAMP pathway results in an enhancement of the 1,25-(OH)2D3 action whereas the protein kinase C pathway attenuates the 1,25-(OH)2D3 action. Finally, the present study provides a basis for the indications from in vivo observations about an interrelated action of 1,25-(OH)2D3 and PTH at the target cell. More generally it demonstrates on the basis of analyses of endogenous cellular responses evidence for an interplay between receptor-activated pathways of peptide and steroid hormones

Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men

In the present cross-sectional study of 403 independently living elderly men, we tested the hypothesis that the decreases in bone mass, body composition, and muscle strength with age are related to the fall in circulating endogenous testosterone (T) and estrogen concentrations. We compared various measures of the level of bioactive androgen and estrogen to which tissues are exposed. After exclusion of subjects with severe mobility problems and signs of dementia, 403 healthy men (age, 73-94 yr) were randomly selected from a population-based sample. Total T (TT), free T (FT), estrone (E1), estradiol (E2), and sex hormone-binding globulin (SHBG) were determined by RIA. Levels of non-SHBG-bound T (non-SHBG-T), FT (calc-FT), the TT/SHBG ratio, non-SHBG-bound E2, and free E2 were calculated. Physical characteristics of aging included muscle strength measured using dynamometry, total body bone mineral density (BMD), hip BMD, and body composition, including lean mass and fat mass, measured by dual-energy x-ray absorptiometry. In this population of healthy elderly men, calc-FT, non-SHBG-T, E1, and E2 (total, free, and non-SHBG bound) decreased significantly with age. T (total and non-SHBG-T) was positively related with muscle strength and total body BMD (for non-SHBG-T, respectively, beta = 1.93 +/- 0.52, P < 0.001 and beta = 0.011 +/- 0.002, P < 0.001). An inverse association existed between T and fat mass (beta = -0.53 +/- 0.15, P < 0.001). Non-SHBG-T and calc-FT were more strongly related to muscle strength, BMD, and fat mass than TT and were also significantly related to hip BMD. E1 and E2 were both positively, independently associated with BMD (for E2, beta = 0.21 +/- 0.08, P < 0.01). Non-SHBG-bound E2 was slightly strongly related to BMD than total E2. The positive relation between T and BMD was independent of E2. E1 and E2 were not related with muscle strength or body composition. In summary, bioavailable T, E1, total E2, and bioavailable E2 all decrease with age in healthy old men. In this cross-sectional study in healthy elderly men, non-SHBG-bound T seems to be the best parameter for serum levels of bioactive T, which seems to play a direct role in the various physiological changes that occur during aging. A positive relation with muscle strength and BMD and a negative relation with fat mass was found. In addition, both serum E1 and E2 seem to play a role in the age-related bone loss in elderly men, although the cross-sectional nature of the study precludes a definitive conclusion. Non-SHBG-bound E2 seems to be the best parameter of serum bioactive E2 in describing its positive relation with BMD

Progression of aortic calcification is associated with metacarpal bone loss during menopause: a population-based longitudinal study

offerosclerosis and osteoporosis are major causes of morbidity and mortality in postmenopausal women and have been suggested to be associated. No study has examined whether progression of atherosclerotic calcification is associated with bone loss. In the present study, we examined progression of aortic calcification, diagnosed by radiographic detection of calcified deposits in the abdominal aorta, in relation to metacarpal bone loss, as assessed by metacarpal radiogrammetry, during menopause. Initially premenopausal women (n=236), aged 45 to 57 years at baseline, were followed for 9 years. We additionally assessed the cross-sectional association between the extent of aortic calcification and metacarpal bone mass and density in 720 postmenopausal women. Twenty-five percent of women going through menopause showed progression of aortic calcification. The average loss of metacarpal bone mass among women with progression of aortic calcification was 3.2 mm(2), and their loss of metacarpal bone density was 7.2 mm(2) %, whereas in women without progression of aortic calcification, these losses were 2.0 mm(2) and 5.6 mm(2) %, respectively, adjusted for age and years of follow-up (P<0.05). Additional adjustment for age at menopause, body mass index, blood pressure, smoking, diabetes mellitus, and use of hormone replacement therapy, thiazide, and loop diuretics did not influence these results. In postmenopausal women, a graded inverse cross-sectional association between the extent of aortic calcification and metacarpal bone mass and density was found. In conclusion, our results indicate that progression of atherosclerotic calcification is associated with increased bone loss in women during menopause