Hypercalciëmie bij sarcoïdose

Bij een 56-jarige man was hypercalciëmie met nierfunctiestoornissen het eerste symptoom dat wees in de richting van sarcoïdose. Het aantonen van verhoogde 1,25-dihydroxyvitamine D-spiegels en van een groep epitheloïde macrofagen in het beenmerg ondersteunde de diagnose. Uiteindelijk kon door het uitsluiten van andere mogelijk granulomateuze afwijkingen en de goede reactie van de hypercalciëmie en de nierfunctiestoornis op behandeling met prednison de diagnose sarcoïdose per exclusionem worden gesteld. De relatie tussen de autonome extrarenale 1,25-dihydroxyvitamine D-produktie en de hypercalciëmie wordt besproken. Op basis hiervan wordt geadviseerd patiënten met sarcoïdose niet aan een overmaat van zonlicht bloot te stellen

Role of calcium and cAMP in heterologous up-regulation of the 1,25-dihydroxyvitamin D3 receptor in an osteoblast cell line

To understand further the mechanism of action of parathyroid hormone (PTH) in the stimulation of the number of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) binding sites in UMR 106-01 cells we studied the role of cAMP and calcium. In addition to PTH other agents known to act via the cAMP signal pathway, prostaglandin E2, forskolin and dibutyryl cAMP, caused an increase in 1,25(OH)2D3 binding. Addition of the adenylate cyclase inhibitor 9-(tetrahydro-2-furyl)adenine resulted in a marked decrease of PTH-stimulated cAMP production but this was not followed by a reduction of 1,25(OH)2D3 receptor up-regulation by PTH. Increasing the intracellular calcium concentration by Bay K 8644 and A23817 independent of an activation of the cAMP signal pathway did not result in an increased 1,25(OH)2D3 binding. The calcium channel blockers nitrendipine and verapamil and chelating extracellular calcium with EGTA all reduced cAMP-mediated stimulation of 1,25(OH)2D3 binding. This reduction was not due to a reduced cAMP production as verapamil even potentiated PTH- and forskolin-stimulated cAMP production in a dose-dependent manner. The present study provides evidence for an interrelated action of calcium and cAMP in the heterologous up-regulation of the 1,25(OH)2D3 receptor. The current data show an interaction between the cAMP and calcium signal pathway at (1) the level of cAMP generation/degradation, and (2) a level located distal in the cascade leading to 1,25(OH)2D3 receptor up-regulation

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

Heterologous up-regulation of the 1,25-dihydroxyvitamin D3 receptor by parathyroid hormone (PTH) and PTH-like peptide in osteoblast-like cells

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) receptor content in cultured osteogenic sarcoma cells (UMR-106) was found to be increased after treatment with both bovine and human PTH and human PTH-like peptide (hPLP). The dose dependent increase of receptors was preceded by a dose dependent stimulation of cAMP production. This suggests a role for cAMP as mediator of the PTH- and hPLP-induced 1,25-(OH)2D3 receptor up-regulation. Furthermore, evidence was obtained that new mRNA and de novo receptor synthesis is involved in this heterologous 1,25-(OH)2D3 receptor up-regulation

The effects of MC903 on 1,25-(OH)2D3 receptor binding, 24-hydroxylase activity and in vitro bone resorption

MC903, a new vitamin D analog has been shown to exert potent effects on cell proliferation and differentiation, while in vivo a decreased activity on calcium metabolism has been observed. In the osteoblast-like cell line UMR-106, MC903 displaces tritiated 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) from its receptor at least as efficiently as 1,25-(OH)2D3. The effect of MC903 on 1,25-(OH)2D3 receptor up-regulation in UMR-106 cells and on bone resorption in fetal mouse radii/ulnae was comparable to that of 1,25-(OH)2D3. MC903 was about 50% less effective in inducing 24-hydroxylase activity and the subsequent C24-side chain oxidation of 25-(OH)D3 compared to 1,25-(OH)2D3. Ketoconazole did not potentiate MC903-induced 1,25-(OH)2D3 receptor up-regulation as was found with 1,25-(OH)2D3 which suggests that the C24-oxidation plays a minor role in the inactivation of MC903. Nevertheless, the comparable effects of MC903 and 1,25-(OH)2D3 on in vitro bone resorption indicate that the lower effectivity of MC903 on bone calcium mobilization in vivo has to be due to a higher metabolic clearance rate

Collagen type I α1 Sp1 polymorphism, osteoporosis, and intervertebral disc degeneration in older men and women

Objectives: To examine whether collagen type I α1 (COL1A1) Sp1 polymorphism is associated with osteoporosis and/or intervertebral disc degeneration in older people. Methods: COL1A1 genotype was determined in 966 men and women (≥65 years) of the Longitudinal Aging Study Amsterdam. The guanine (G) to thymidine (T) polymorphism in the first intron of the COL1A1 gene was detected by PCR and Mscl digestion. In the total sample, quantitative ultrasound (QUS) measurements, serum osteocalcin (OC), and urine deoxypyridinoline (DPD/Crurine) were assessed. A follow up of fractures was done every three months. In a subsample, total body bone mineral content (n = 485) and bone mineral density (BMD) of the hip and lumbar spine (n = 512) were measured by dual energy x ray absorptiometry (DXA). Prevalent vertebral deformities and intervertebral disc degeneration were identified on radiographs (n = 517). Results: People with the TT genotype had a higher risk of disc degeneration than those with the GG and GT genotypes (OR = 3.6; 95% CI 1.3 to 10). For men, higher levels of OC were found in those with the T allele than in those without it (GG v (GT+TT) 1.96 (0.06) nmol/l v 2.19 (0.09) nmol/l). COL1A1 polymorphism was not significantly associated with other measures of osteoporosis in either men or women. Conclusion: COL1A1 Sp1 polymorphism may be a genetic risk factor related to intervertebral disc degeneration in older people. Previously reported associations between the COL1A1 Sp1 genotype and lower BMD or QUS values, higher levels of DPD/Cr, and an increased fracture risk in either men or women could not be confirmed

Age‐associated changes in ultrasound measurements of the calcaneus in men and women:The rotterdam study

Broadband ultrasound attenuation (BUA) and speed of sound (SOS) of the os calcis were measured in a sample of 1405 persons (628 men), aged 55–93 years, from the cohort of the Rotterdam Study, a population‐based study of diseases in the elderly. We studied the effect of age, body mass index, age at menopause, current use of thiazides, loop diuretics, and estrogens, smoking, and disability on SOS and BUA. Comparisons were made between ultrasound measurements and bone mineral density (BMD) measurements of the lumbar spine and proximal femur using DXA. We found a significant decline with age in SOS and BUA in men (‐0.4 and −0.1 %/year, respectively) and women (‐1.3 and −0.4%/year, respectively), which persisted after adjustment for body mass index. Age at menopause was not associated with SOS or BUA. Pack‐years of smoking was negatively related to SOS in both sexes and to BUA in men. Severe disability was associated with lower SOS and BUA in men, but not in women. Despite the small number of exposed persons, current corticosteroid use was associated with lower BUA in men. The other risk factors examined did not affect the ultrasound measurements. We observed modest correlations between SOS or BUA, on the one hand, and BMD of the lumbar spine, on the other hand (r = 0.32–0.42). Similar correlations were found between ultrasound measurements and BMD measurements of the proximal femur. We conclude that in persons 55 years or over (1) there is a significant age‐related decline of BUA and SOS, which is about three times higher in women compared with men, and (2) ultrasound measurements are not able to predict low BMD in hip or spine.</p

Consequences of vitamin D receptor regulation for the 1,25-dihydroxyvitamin D3-induced 24-hydroxylase activity in osteoblast-like cells: Initiation of the C24-oxidation pathway

A direct relationship between vitamin D receptor (VDR) level and target cell responsiveness to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) has been shown in osteoblast-like cell lines. However, we previously found an inverse relationship between the TGFβ-induced VDR up-regulation and subsequent 1,25-(OH)2D3-induced biological responses. A clear inhibition of the 1,25-(OH)2D3-induced stimulation of osteocalcin and osteopontin expression was observed. A biological response that has formerly been shown do be coupled to VDR level is 24-hydroxylase activity. This enzyme initiates the C24 oxidation of the side-chain, followed by cleavage and ultimate metabolic clearance of both 25-(OH)D3 and its metabolite 1,25-(OH)2D3. With UMR 106 (rat) and MG 63 (human) osteoblast-like cells, we show that after preincubation with TGFβ, which causes an increase in VDR level, 1,25-(OH)2D3 induction of 24-hydroxylase activity is also stimulated. In addition, we provide evidence that variations in VDR level induced by other means (PTH, EGF, medium change) are also closely associated with 1,25-(OH)2D3-induced 24-hydroxylase activity. Furthermore, we show that in MG 63 cells, but not in UMR 106 cells, TGFβ itself was able to increase the activity of the enzyme 24-hydroxylase. As 24-hydroxylation is the initial step in the further C24 oxidation of 1,25-(OH)2D3, our results indicate a close coupling of VDR level and the degradation of its ligand, 1,25-(OH)2D3. This mechanism may provide an important regulatory feedback in the action of 1,25-(OH)2D3 at target tissue/cell level