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PubMed1996

Parathyroid hormone related peptide mRNA expression during murine postimplantation development: evidence for involvement in multiple differentiation processes.

In this study we describe the spatio-temporal expression of Parathyroid Hormone related Peptide (PTHrP) mRNA during murine postimplantation development from day 5.5 post coitum (pc) until day 12.5 pc. From day 5.5 pc and onwards PTHrP mRNA was detected in the trophoblast. In addition, at day 5.5 and 6.5 pc epithelial cells of the antimesometrial crypt and cells of the inner zone of the decidua directly adjacent to the implanted embryo expressed PTHrP mRNA. This supported a previous model in which parietal endoderm formation is regulated by a paracrine mechanism involving PTHrP expressing trophoblast cells and receptor expressing extra-embryonal endoderm cells. The first embryonal PTHrP mRNA expression was detected in the roof of the hindbrain at gestation day 10.5 pc. From day 11.5 pc and onwards PTHrP mRNA was detected in the otic vesicle, the semilateral channels, the roof of the hindbrain and later in the choroid plexus, in epithelial cells of the lung and heart ventricle, mesenchymal cells lining the nasal pit, the dermis of the snout and at all sites of endochondral bone formation. The widespread expression of PTHrP mRNA during embryogenesis in extra-embryonic and embryonic tissues suggests the involvement of the peptide in multiple growth and differentiation processes.

Animals↗
PubMed1985

Mapping parathyroid hormone, beta-globin, insulin, and LDH-A genes within the human chromosome 11 short arm by spot blotting sorted chromosomes.

Rearranged human chromosomes carrying segments of chromosome 11 were separated from the normal chromosome 11 by high-resolution chromosome sorting. Sorted chromosomes were tested with parathyroid hormone, beta-globin, insulin, and LDH-A gene-specific probes to determine the genes carried by each chromosome segment. Based on the gene content and karyotypes of these abnormal chromosomes, the parathyroid hormone, beta-globin, insulin, and LDH-A genes and the unique restriction fragment ADJ-762 are all located on the terminal band of the short arm of human chromosome 11 (band 11p15), with LDH-A proximal to the other loci.

Animals↗
PubMed1996

Structure of recombinant human parathyroid hormone in solution using multidimensional NMR spectroscopy.

The solution structure of human parathyroid hormone, in the form of recombinant prolyl-hPTH(1-84), has been investigated by multidimensional NMR spectroscopy under conditions (aqueous trifluoroethanol) which favour the structured-state of the protein. Spin systems were identified from 3D 1H DQF (double-quantum filtered)-COSY and TOCSY spectra and sequence-specific assignments were from 2D 1H phase-sensitive NOESY spectra. Signal overlap was resolved in a 3D-NOESY-TOCSY spectrum and assignments were confirmed with 2D NOESY-15N-HMQC (heteronuclear multiple-quantum coherence) spectra taken of a sample universally labeled with 15N. A satisfactory set of final structures was calculated from the quantitative NOE data using restrained molecular dynamics and energy minimization calculations. The N-terminus is dominated by three, well defined helices between Ser-3 to Asn-10, Ser-17 to Lys-27 and Asp-30 to Leu-37, while the most significant structural features in the C-terminus are a short, less-well defined helix between Asn-57 to Ser-62 and a series of loose turns. These two terminal units are joined by an unstructured mid-region. The molecule shows a tendency towards tertiary structure, defined by a number of long-range NOEs. A detailed RMS deviation analysis allowed the final refined structures to be classified into a limited ensemble of stable conformations that reflect the inherent flexibility of the hormone in solution.

Amino Acid Sequence↗
PubMedDate not supplied

Parathyroid hormone responsiveness in hypoparathyroidism with hypomagnesemia.

The failure to respond normally to parathyroid hormone (PTH) administration has been reported in patients with severe hypomagnesemia. A patient with hypoparathyroidism and a markedly decreased serum concentration of magnesium (0.7 mEq/liter), but a normal red blood cell magnesium level, is described who increased serum calcium concentration and decreased per cent renal tubular reabsorption of phosphate when parathyroid extract was given. It is suggested that PTH responsiveness in hypomagnesemic patients may, at least in part, be dependent upon the adequacy of intracellular magnesium stores. This interpretation is supported by the normal cellular (red blood cell) magnesium concentrations observed in this patient and in comparable studies in which PTH responsiveness in the presence of hypomagnesemia was demonstrated. In addition, a failure of optimal renal conservation of magnesium was noted to occur in this patient since, despite hypomagnesemia, urinary magnesium excretion was greater than the 1 mEq/day loss that is seen when magnesium conservation is induced by means such as dietary restriction.

Aged↗
PubMed2001

Identification of signal transduction pathways and promoter sequences that mediate parathyroid hormone 1-38 inhibition of osteoprotegerin gene expression.

Osteoprotegerin (OPG), a secreted member of the tumor necrosis receptor superfamily, is a potent inhibitor of osteoclast formation and bone resorption. Parathyroid hormone (PTH), a potent inducer of osteoclast formation, suppresses OPG mRNA expression in vitro and in vivo. To determine the molecular basis of this inhibition, we analyzed the effects of PTH on the human OPG promoter (-5917 to +19) fused with beta-galactosidase reporter gene in stable and transient transfections into rat osteoblast-like UMR106 cells. The effect of PTH on OPG promoter expression was biphasic and concentration-dependent. PTH (1-100 nM) induced the transcriptional activity of the OPG promoter (1.7-fold) at 8 h followed by a gradual decrease with maximal inhibition (6.6-fold) at 24-48 h. To ascertain the signal transduction pathways mediating PTH (1-38) effects on OPG gene expression, we compared the effects of PTH with PTH analogs, parathyroid hormone-related protein 1-34 (PTHrP 1-34), forskolin, 3-isobutyl-1-methylxanthine (IBMX), dibutyryl cAMP, phorbol-12-myristate-13-acetate (PMA), thapsigargin and calcium ionophore A23187. PTH 1-31 and PTHrP 1-34, which stimulate the cAMP/PKA pathway, and other activators of cAMP/PKA, forskolin, IBMX, N(6), O(2')-dibityryl adenosine 3',5'-cyclic monophosphate (dibutyryl cAMP), all elicited a similar biphasic response on OPG promoter expression. PTH analogs PTH 3-34 and PTH 7-34, that do not stimulate cAMP production, had no effect on OPG expression. In contrast, phorbol-12-myristate-13-acetate (PMA), an activator of PKC, stimulated OPG promoter expression, while thapsigargin and calcium ionophore A23187, which increase intracellular Ca(2+), showed a dose-dependent inhibition of OPG promoter expression. To delineate the promoter sequences that mediate the inhibitory effects of PTH on OPG transcription, we analyzed systematic deletions of the OPG promoter for responsiveness in transient transfection assays. The major inhibitory effects of PTH were localized to 391 bp (-372 to +19) of the proximal promoter. Deletions of the promoter region led to a complete loss of responsiveness. Taken together, these results demonstrate that the inhibitory effects of PTH on OPG are mediated at the transcriptional level through cis elements in the proximal promoter. The similar biphasic response of OPG to PTH, PTH 1-31, PTHrP 1-34, forskolin, IBMX and dibutyryl cAMP suggests that PTH regulates OPG transcription via activation of the cAMP/PKA signal transduction pathway.

1-Methyl-3-isobutylxanthine↗
PubMed1989

Structure-activity relationships of parathyroid hormone analogs in the opossum kidney cell line.

Structural alterations in the parathyroid hormone (PTH) molecule produce marked changes in biologic activity. We examined the relative sensitivity of PTH-stimulated cAMP formation and PTH-inhibitable Na+-dependent phosphate transport responses to bovine PTH analogs [bPTH-(1-34), bPTH-(1-84), 8,18-norleucine-34-tyrosinamide bPTH-(1-34), bPTH-(7-34)-amide, 8,18-norleucine-34-tyrosinamide bPTH-(3-34), transaminated bPTH-(1-34)] and the human PTH-related peptide of malignancy (1-34) in cultured opossum kidney cells. The rank order of potency for stimulation of cAMP formation was bPTH-(1-34) = hPTHrP-(1-34) greater than nle bPTH-(1-34) greater than bPTH-(1-84) much greater than TAbPTH-(1-34). Nle bPTH-(3-34) and bPTH-(7-34) did not affect cAMP formation in intact cells at concentrations up to 10 microM. The rank order of potency for the inhibition of phosphate transport was bPTH-(1-34) = hPTHrP-(1-34) greater than nle bPTH-(1-34) greater than bPTH-(1-84) = TAbPTH-(1-34) greater than nle bPTH-(3-34). TAbPTH-(1-34) was a full agonist and inhibited phosphate transport at concentrations that did not increase cAMP formation, but nle bPTH-(3-34) was a partial agonist in spite of its inability to stimulate cAMP formation. Bovine PTH-(7-34) had no effect on phosphate transport. This study indicates that changes in the PTH molecule produce analogs that apparently discriminate between the cAMP-stimulating activity and phosphate transport-inhibiting activities of the native hormone.(ABSTRACT TRUNCATED AT 250 WORDS)

Amination↗
PubMed2006

Unexpected serum parathyroid hormone profiles in some patients with primary hyperparathyroidism.

BACKGROUND: Third-generation parathyroid hormone (PTH) assays have been reported to measure only intact PTH(1-84), in contrast to second-generation assays, which also detect PTH(7-84) fragments. Higher PTH measurements were observed with third- than with second-generation PTH assays in a few patients with either severe primary hyperparathyroidism or parathyroid carcinoma. METHODS: We analyzed biological data [second- and third-generation PTH assays, 25-hydroxyvitamin D (25-OHD), calcium, and phosphate concentrations] obtained before and after surgery for 2 groups of patients selected from a large series of consecutive patients with primary hyperparathyroidism (PHPT): 7 female patients with surgically and histologically confirmed PHPT (group 1) and a matched group (group 2). RESULTS: For group 1 but not group 2, PTH concentrations measured by third-generation PTH assays before surgery were higher than those measured by the second-generation assays. Circulating 25-OHD, calcium, and phosphate concentrations were similar in both groups. In addition, PTH values measured with the third-generation PTH assays in group 1 decreased after surgery. CONCLUSIONS: Our results confirm that third-generation PTH assays do not measure only PTH(1-84). The frequency of this unexpected finding of markedly lower PTH concentrations than previously reported was approximately 5% in patients with PHPT without malignancy. We do not know whether the presence of this unexpected profile is predictive of malignancy.

Adult↗
PubMed1990

Parathyroid hormone, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentration in elderly patients.

In 50 patients of a geriatric hospital (33 women, aged 65-96 years, mean age 80 years, and 17 men, aged 68-91, mean age 78.3 years) calcium, albumin, phosphate, urea, creatinine, parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were determined. Forty patients with serum creatinine levels up to 1.4 mg/dl (124 mumols/l) and 10 patients with creatinine concentrations greater than or equal to 1.5 mg/dl (132 mumols/l) were evaluated. In patients with normal creatinine, a positive correlation was found between parathyroid hormone and age (r = 0.41; P less than 0.01). In patients with elevated creatinine, negative correlations were found in 1,25-dihydroxyvitamin D and calcium (r = -0.724; P less than 0.05), 1,25-dihydroxyvitamin D and creatinine (r = -0.79; P less than 0.01) and 1,25-dihydroxyvitamin D and phosphate (r = -0.87; P less than 0.002). The best correlation was observed in patients with elevated serum creatinine for 1,25-dihydroxyvitamin D and phosphate (r = -0.91; P less than 0.001). The results suggest that low levels of calcium and phosphate stimulate the 1-hydroxylation of 25-hydroxyvitamin D even in advanced age and that the calcium metabolism of these patients is frequently disturbed. Nineteen patients had low levels of 25-hydroxyvitamin D, indicating an insufficient supply of vitamin D or rare exposure to sunlight. In 49 of 50 patients, one ore more of the parameters of calcium metabolism were outside the normal range.

Aged↗
PubMed1988

Parathyroid hormone receptors in human dermal fibroblasts: structural and functional characterization.

Previous studies have established the presence of parathyroid hormone (PTH)-sensitive adenylate cyclase activity in cultured human skin fibroblasts. The present study was undertaken to identify and quantitate PTH receptors directly in such cells. Human dermal fibroblast cell line CRL 1564 was found to possess specific binding sites for [125I]PTH(1-34). These sites bound PTH selectively; bovine and human PTH(1-34) and PTH(1-84) competed for [125I]PTH(1-34) binding sites, whereas the unrelated peptides calcitonin, insulin, AVP, angiotensin II, and ACTH(1-24) were inactive even at micromolar concentrations. Competitive binding experiments demonstrated the presence of binding site heterogeneity. These data fit a "two-site" model (p less than 0.001) in which one binding component has high affinity (Kd = 2.5 ng/ml = 0.6 nM) and low capacity (10(4) sites/cell) while the other has low affinity (Kd = 5.9 micrograms/ml = 1.5 microM) and high capacity (greater than 10(7) sites/cell). Similar high- and low-affinity [125I]bPTH(1-34) binding sites were seen also in CRL 1564 membranes containing a PTH-responsive adenylate cyclase. The Kd of the high-affinity sites was identical to the concentration of unlabeled bPTH(1-34) (4.2 ng/ml = 1.0 nM) required to half-maximally elevated cyclic AMP in CRL 1564 cells. Affinity labeling of specific PTH binding sites revealed the presence of multiple components with Mrs of 85, 70, 40, 33, and 23 kD on SDS-PAGE. Competition experiments did not disclose structurally discrete high- and low-affinity sites. Thus, structurally homologous PTH receptors in human skin fibroblasts apparently can assume two affinity states: (i) a high-affinity state coupled to adenylate cyclase and (ii) a low-affinity state that may represent uncoupled receptors.

Adenylyl Cyclases↗
PubMed1990

Two-site assay of intact parathyroid hormone in primary hyperparathyroidism: studies in basal conditions, following adenoma removal and during calcium and EDTA infusion.

This study has been carried out in order to investigate parathyroid hormone secretion in patients with primary hyperparathyroidism in basal conditions, during stimulation and suppression tests and following successful surgery. Parathyroid gland secretory activity has been evaluated by a highly sensitive immunoradiometric assay (IRMA) which detects only the biologically intact active hormone and with a well established midmolecule (MM) PTH RIA. There was a good correlation between the two assays in basal state (r = 0.779); however the correlation found between serum PTH levels and total calcium values was better for the intact hormone (P less than 0.001) than for the radioimmunoassay (P less than 0.05). Twenty-four hours following surgery, serum intact PTH levels were in all patients less than 10 pg/ml while midmolecule PTH was still detectable, thereafter remaining at a higher level during the next six days. Serum IRMA PTH levels fell rapidly in response to the increase in serum calcium, then there was a trend to reach a plateau; serum midregion PTH levels fell, although slower than those of intact hormone. The percent increase obtained for serum intact hormone levels was higher than that observed for MM RIA, following EDTA stimulation. The results obtained indicate that the assays of intact and midmolecule parathyroid hormone clearly reflect different aspects of hormone metabolism 'in vivo' and may prove therefore to be useful for its investigation in various calcium disorders.

Adenoma↗
PubMed1976

Relative effectiveness of magnesium and calcium on the secretion and biosynthesis of parathyroid hormone in vitro.

The effects of varying extracellular concentrations of calcium and magnesium were compared on the release of 3H-labeled and immunoreactive parathyroid hormone (PTH) by bovine parathyroid slices incubated for 4 h in vitro in media containing [3H]leucine. The quantity of [3H]PTH or immunoreactive PTH released was determined by polyacrylamide gel electrophoresis and by radioimmunoassay, respectively. Biosynthesis of PTH in response to extracellular concentrations of magnesium and calcium was evaluated by radioimmunoassay of amounts of proparathyroid hormone (PROPTH) in extracts of the parathyroid tissues and by electrophoretic analyses of [3H]ProPTH synthesized during a 35 min pulse-labeling of parathyroid slices. Rates of hormone release were found to vary in response to changes in concentrations of either calcium or magnesium. The effects, however, of these two cations on hormone release, although additive, were not equipotent. On a molar basis, approximately 2.5 times as much magnesium as calcium was required to produce equivalent secretory responses. Effects of the cations on hormone biosynthesis wer small; magnesium had no effect and calcium altered synthesis by approximately 15%. Neither cation affected conversion of ProPTH to PTH. The results agree with those reported previously from studies of the effects on hormone secretion of calcium and magnesium in vivo and serve to emphasize that, within normal physiological concentrations of these two cations, calcium is the predominant regulator of PTH secretion and synthesis.

Animals↗
PubMed2006

Understanding parathyroid hormone action.

In addition to regulating serum calcium and stimulating bone resorption, parathyroid hormone (PTH) is known to stimulate bone formation under certain conditions. The mechanisms behind this counterintuitive anabolic action are largely unknown. We have set out to identify PTH-regulated genes that might be responsible for each of these contrasting effects of the hormone. This article describes our work on a select number of those genes.

Amphiregulin↗
PubMed1994

Purification of meprin from human kidney and its role in parathyroid hormone degradation.

Meprin (EC 3.4.24.18) is known to occur in the kidneys of mice and rats, but has not previously been found in human kidneys. Here we report the isolation of meprin from human kidney and show that it has a role in the degradation of parathyroid hormone (PTH) in that organ. The purified human meprin had properties almost identical to those of rat meprin including molecular size, substrate specificity and inhibitor sensitivity, and it also cross-reacted well with an antibody raised against rat meprin. Both the purified human meprin and the microvillar membranes of human kidney readily hydrolyzed human parathyroid hormone [hPTH-(1-84)] into several fragments, whose amino acid sequences corresponded well to each other. Thus, meprin appears to play a major role in the PTH-degrading activity in the microvillar membranes of human kidney. Our results indicate that meprin, which so far has mainly been investigated in mice and rats, is found not only in these rodents, but also in the human kidney, and suggest that its physiological role in humans is to degrade PTH in the kidney.

Amino Acid Sequence↗
PubMed1998

High-level production of recombinant human parathyroid hormone 1-34.

Expression of the synthetic human parathyroid hormone 1-34 [hPTH(1-34)] gene by a gene fusion strategy was demonstrated. hPTH(1-34) was produced at the C terminus of the partner peptides involving amino acids 1 to 97, 1 to 117, or 1 to 139 of a modified Escherichia coli beta-galactosidase by linker peptides containing oligohistidine of different lengths. The fusion proteins in the inclusion bodies were rendered soluble with urea and subjected to site-specific cleavage with the secretory type yeast Kex2 protease. Optimal expression and enzymatic processing were achieved in the fusion protein beta G-117S4HPT, constructed from amino acids 1 to 117 of beta-galactosidase and the linker of HHHHPGGSVKKR. The fusion protein accumulated more than 20% of the E. coli total protein. The hPTH(1-34) was purified up to 99.5% with a good yield of 0.5 g/liter of culture. The purified product was identified as intact hPTH(1-34) by amino acid analysis and N-terminal sequencing.

Humans↗
PubMed1974

Influence of sodium and parathyroid hormone on calcium release from intestinal mucosal cells.

The uptake and release of (45)Ca from the intestinal mucosal epithelium were investigated under a variety of conditions. The initial rate of uptake characterized a calcium pool with a half-time of saturation of less than 2 min. The entry of (45)Ca into this pool was inhibited by NaCN and ethacrynic acid and was stimulated by the removal of Cl(-) from the incubation. The initial rate of (45)Ca release was also inhibited by NaCN and removal of Na(+) from the incubation. Parathyroid hormone administration enhanced the release of (45)Ca from cells prepared from parathyroid-ectomized animals. These observations suggest that calcium transport across the brush border and basallateral membranes are identifiable components of the kinetics of (45)Ca uptake and release and that parathyroid hormone stimulates a sodium-dependent mechanism of calcium transport across the basal-lateral membranes.

Animals↗
PubMed1994

Changes in parathyroid hormone receptors during chondrocyte cytodifferentiation.

The purpose of this study was to investigate the relationship between changes in parathyroid hormone (PTH) receptor levels and chondrocyte maturation during endochondral ossification. Chondrocytes were isolated from the growth plate of rabbit ribs and maintained in the presence of 10% serum in mass cultures. Treatment with PTH-(1-84) and a PTH-(1-34) fragment suppressed the increases in alkaline phosphatase activity and in type X collagen and 1 alpha,25-dihydroxyvitamin D3 receptor levels and abolished 45Ca incorporation into mineral, all of which occurred in parallel untreated cultures in the hypertrophic (terminal) stage. These effects of PTH were observed at low concentrations (10(-10) to 10(-9) M) and within 24-48 h of treatment. PTH-(1-84) and PTH-(1-34) also increased [35S]sulfate incorporation into newly synthesized proteoglycans. In contrast, the middle and carboxyl-terminal fragments of PTH tested had little effect on proteoglycan synthesis or terminal differentiation. The binding of 125I-PTH-(1-34) to cells in the growth plate was greater than that to cells in liver, skin, muscle, brain, or kidney. When the correlation between binding levels and stage of maturation was examined, we found that 125I-PTH-(1-34) binding to its 72-kDa receptor was low in resting and proliferating chondrocytes, increased 10-fold in matrix-forming chondrocytes, and thereafter decreased in hypertrophic chondrocytes both in vitro and in situ. Scatchard analysis revealed that the changes in PTH binding were due to changes in the number, and not in the affinity, of the receptor. The changes in PTH-(1-34) binding paralleled those in [35S]sulfate incorporation into proteoglycans. These findings suggest that stage-dependent increases in PTH/PTH-related peptide receptor levels localize the hormone stimulation of proteoglycan synthesis and inhibition of precocious hypertrophy in the matrix-forming zone of growth plates.

Alkaline Phosphatase↗
PubMed1998

Induction of osteoclast formation by parathyroid hormone depends on an action on stromal cells.

It is believed that parathyroid hormone (PTH) increases the resorptive activity of pre-existing osteoclasts through a primary interaction with cells of the osteoblastic lineage. Much less is known, however, of the mechanisms by which PTH induces osteoclast formation. It is known that osteoclast formation occurs through a contact-dependent interaction between stromal cells and haemopoietic precursors, but it is not known whether PTH acts on stromal cells or precursors to induce osteoclast formation. To address this issue, we compared the ability of haemopoietic cultures to generate osteoclasts, identified as calcitonin receptor positive (CTRP) cells, and to resorb bone in response to PTH and 1,25(OH)2 vitamin D3 (1,25(OH)2D3). We found that when murine haemopoietic tissues were incubated at densities sufficiently high to support haemopoiesis, both PTH and 1,25(OH)2D3 induced bone resorption in bone marrow cells, but in cultures of haemopoietic spleen only 1,25(OH)2D3 induced CTRP cells, and neither hormone induced bone resorption. To determine whether these differences were attributable to differences in stromal cells or haemopoietic precursors, lower densities of haemopoietic spleen cells were incubated on osteoblastic (UMR 106), splenic or bone marrow stromal cells. We found that the behaviour of the cocultures reflected the characteristics and origin of the stromal cells. Thus, the ability of both osteoblastic and splenic stromal cells to induce CTRP cells with 1,25(OH)2D3, while only osteoblastic cells induced osteoclasts with PTH, from the same precursors, suggests that the ability of PTH to induce osteoclastic differentiation cannot be attributed to a hormonal action on osteoclast precursors, but depends on a response in stromal cells.

Animals↗
PubMed2002

Mechanisms of the regulation of EGF receptor gene expression by calcitriol and parathyroid hormone in UMR 106-01 cells.

BACKGROUND: We have previously demonstrated that parathyroid hormone (PTH) and calcitriol increase the expression of epidermal growth factor receptors (EGFR) in UMR 106-01 osteoblast-like cells. The effect of PTH is mediated by cAMP and it involves an increase in the level of EGFR mRNA. The present studies were designed to investigate the mechanisms involved in the regulation of EGFR expression by PTH and calcitriol. METHODS: To examine the mechanism of the effect of calcitriol on EGFR expression, confluent cultures of UMR 106-01 cells were exposed to calcitriol and levels of EGFR mRNA were determined by reverse transcription-polymerase chain reaction (RT-PCR). In order to study the effect of calcitriol on EGFR gene transcription, a candidate vitamin D-responsive element (VDRE) was identified in the EGFR gene promoter and complimentary 30-mer oligonucleotides spanning this region were tested for binding to recombinant VDR using EMSA. Transcriptional activity in response to calcitriol and PTH was tested in UMR 106-01 cells stably transfected with a luciferase reporter construct containing the full length EGFR gene promoter. The effect of calcitriol on EGFR mRNA stability was examined in transcriptionally arrested cells. RESULTS: Treatment with calcitriol resulted in a time and dose dependent increase in EGFR mRNA levels in confluent cultures of UMR 106-01 osteoblast-like cells. Using EMSA, we demonstrated that the putative human EGFR VDRE binds to recombinant VDR in a retinoid X receptor (RXR)-dependent manner; however, calcitriol failed to increase transcriptional activity from a luciferase reporter construct containing the full-length EGFR gene promoter in stably transfected UMR 106-01 cells. Therefore, EGFR mRNA degradation was examined in transcriptionally arrested cells and calcitriol was found to prolong the half life of EGFR mRNA. Treatment of the cultures with PTH resulted in a ninefold increase in luciferase activity after four hours of exposure, a finding that was reproduced by treatment with forskolin. CONCLUSIONS: These studies demonstrate that the calciotropic hormones PTH and calcitriol increase EGF receptor expression by different mechanisms. The former increases EGFR gene transcription whereas the latter increases EGFR mRNA stability.

Calcitriol↗