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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 5 2000-2003
Copyright © 2000 by The Endocrine Society

Original Studies

Reduced Parathyroid Vitamin D Receptor Messenger Ribonucleic Acid Levels in Primary and Secondary Hyperparathyroidism1

Tobias Carling, Jonas Rastad, Eva Szabó, Gunnar Westin and Göran Åkerström

Endocrine Surgery Unit, Department of Surgery, Uppsala University Hospital, S-751 85 Uppsala, Sweden

Address correspondence and requests for reprints to: Tobias Carling, Ph.D., M.D., Endocrine Surgery Unit, Department of Surgery, Uppsala University Hospital, S-751 85 Uppsala, Sweden. E-mail: Tobias.Carling{at}kirurgi.uu.se


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Vitamin D, via its receptor (VDR), inhibits the hormone secretion and proliferation of parathyroid cells. Vitamin D deficiency and reduced parathyroid VDR expression has been associated with development of hyperparathyroidism (HPT) secondary to uremia. VDR polymorphisms may influence VDR messenger RNA (mRNA) levels and have been coupled to an increased risk of parathyroid adenoma of primary HPT. VDR mRNA relative to glyceraldehyde-3-phosphate dehydrogenase mRNA levels were determined by RNase protection assay in 42 single parathyroid adenomas of patients with primary HPT, 23 hyperplastic glands of eight patients with uremic HPT, and 15 normal human parathyroid glands. The adenomas and hyperplasias demonstrated similar VDR mRNA levels, which were reduced (42 ± 2.8% and 44 ± 4.0%) compared with the normal glands (P < 0.0001). Comparison of parathyroid adenoma with a normal-sized parathyroid gland of the same individual (n = 3 pairs) showed a 20–58% reduction in the tumor. Nodularly enlarged glands represent a more advanced form of secondary HPT and showed greater reduction in the VDR mRNA levels than the diffusely enlarged glands (P < 0.005). The reduced VDR expression is likely to impair the 1,25(OH)2D3-mediated control of parathyroid functions, and to be of importance for the pathogenesis of not only uremic but also primary HPT. Circulating factors like calcium, PTH, and 1,25(OH)2D3 seem to be less likely candidates mediating the decreased VDR gene expression in HPT.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ACTIVE VITAMIN D (1, 25(OH)2D3), via its receptor [VDR or NR1I1 (1)], inhibits PTH secretion and parathyroid cell proliferation (2, 3, 4). Both primary hyperparathyroidism (HPT) and HPT secondary to uremia are characterized by PTH hypersecretion and enhanced parathyroid cell proliferation, which could relate to derangements in the regulation by 1,25(OH)2D3-VDR. Only uremic HPT, however, has consistently been associated with reduced parathyroid VDR expression (5, 6). This reduction seems to aggravate with progression of the secondary parathyroid hyperplasia from diffuse to nodular within the enlarged glands (6). These findings concur with the notion that resistance to 1,25(OH)2D3 treatment can occur in more advanced stages of HPT secondary to uremia (7).

Previous ligand-binding studies have suggested a normal level of expression of the VDR protein in parathyroid adenomas of primary HPT (8), whereas a recent immunohistochemical analysis supported VDR down-regulation in such adenomas (9). Genetic association studies substantiate a pathogenic role of VDR in primary HPT, since the VDR alleles b, a, and T have been found to be associated with reduced VDR messenger RNA (mRNA) levels, enhanced resistance of the PTH secretion to calcium, and an increased risk of developing HPT (10, 11, 12, 13, 14). The present study demonstrates that VDR mRNA levels are reduced to a similar extent in parathyroid adenomas of primary HPT and hyperplasias secondary to uremia.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissues and subjects

Parathyroid adenoma specimens were obtained from 42 patients with nonfamilial primary HPT. None of them had a history of familial hypercalcemia, signs of multiple endocrine neoplasia syndromes, or substantially raised serum creatinine levels (Table 1Go). These patients have been analyzed for parathyroid gene expression as part of other studies, and the VDR mRNA levels have been presented in relation to VDR genotypes (14, 15). Twenty-three hyperplastic parathyroid glands were gathered from eight patients with HPT secondary to uremia (Table 1Go). All patients with secondary HPT were hypercalcemic, and their serum PTH levels ranged between 200 and 2400 ng/L. Biopsies of normal human parathyroid glands (n = 15) were obtained from 15 normocalcemic patients operated for atoxic goiter. These were excised due to macroscopic ambiguity on the microscopic diagnosis. In addition, matched normal parathyroid tissue from an associated gland was obtained from 3 of the 42 patients with primary HPT due to parathyroid adenoma. All parathyroid glands were analyzed histopathologically by use of conventional criteria (16). Total serum calcium was determined by atomic absorption and corrected for albumin (reference range, 2.20–2.60 mM). Intact serum PTH was measured with the Allegro Immunometric assay (Nichol’s Institute, San Juan, CA). Serum creatinine (reference range, 60–106 µmol/L) and the total alkaline phosphatases (reference range, 0.8–4.8 µkat/L) were analyzed by routine methods. The study was approved by the Ethical Committee of the Uppsala University.


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  		Table 1. Clinical characteristics of the euparathyroid patients and those with primary and secondary HPT

 
RNA isolation

Biopsies (25–150 mg) of the parathyroid glands were intraoperatively snap-frozen and stored at -70 C. The tissues was pulverized in liquid nitrogen, and total RNA was isolated by standard procedures (17), or by using the TRIZOL reagent (Life Technologies, Inc.), according to the vendor’s instructions. Approximately 2 µg total RNA was run on an ethidium-bromide-stained agarose gel to analyze the RNA quality.

RNase protection assay

Total RNA from the parathyroid glands was analyzed by the RNase protection assay, as described (14). Briefly, radiolabeled antisense RNA for VDR and glyceraldehyde-3-phosphate dehydrogenase (GAPDH; Ambion, Inc., Austin, TX) were produced by in vitro transcription from linearized plasmids using T3 or T7 RNA polymerase (Stratagene, La Jolla, CA) and [{alpha}-32P]UTP (Amersham Pharmacia Biotech, Little Chalfont, UK). Total RNA (5–10 µg) was hybridized overnight to excess 32P-labeled VDR and GAPDH. The samples were run on a 6%/7 M urea polyacrylamide gel, and the bands were quantified by PhosphorImager analysis (Molecular Dynamics, Inc., Sunnyvale, CA) after overnight exposure. The VDR mRNA value of each specimen was corrected by use of the GAPDH mRNA level as an internal standard. Gel electrophoresis showed no signs of reduced mRNA levels due to RNase activity, and insufficient total RNA quality was no cause for exclusion of any of the samples. GAPDH mRNA levels were similar in the normal and abnormal parathyroid glands.

Statistical analysis

Differences in mean values were calculated with an unpaired t test using a P < 0.05 significance level. Regression analysis was performed with Statview 4.0.2 (Abacus, Berkeley, CA). Values are presented as mean ± SEM, whereas the glandular weight is presented as geometrical mean ± SEGM.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
VDR mRNA expression was substantiated in all the normal and pathological parathyroid glands by use of the RNase protection assay. The relative VDR mRNA levels (adjusted for GAPDH) were 42 ± 2.8% (range, 8–72%) lower in the parathyroid adenomas as compared with the normal human parathyroid glands (P < 0.0001; Fig. 1Go). Also the hyperplasias of secondary HPT demonstrated a significantly reduced VDR mRNA expression (mean, 44 ± 4.0%; range, 23–88%) compared with the normal glands (P < 0.0001). No significant difference in relative VDR mRNA expression was noted between the adenomas and secondary hyperplasias (P = 0.66). The VDR/GAPDH mRNA ratio values for the adenomas, secondary hyperplasias, and normal parathyroid glands were 0.057 ± 0.003, 0.060 ± 0.006, and 0.136 ± 0.009, respectively.



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  		Figure 1. By use of the RNase protection assay, the relative VDR mRNA levels (VDR/GAPDH ratio) were determined from total RNA extracted from parathyroid specimens, as described (14 ). Values are mean ± SEM for the indicated number of investigated parathyroid glands. *, P < 0.0001 vs. normal parathyroid glands; {dagger}, P < 0.005 vs. diffuse secondary hyperplasia. P values are calculated with unpaired t test.

 
Matched parathyroid adenoma and normal parathyroid tissue from the same patient was available in three cases. The relative VDR mRNA levels were reduced in all three adenomas, with a mean VDR/GAPDH mRNA ratio of 0.051 ± 0.023 vs. 0.143 ± 0.009 for the normal glands (P < 0.005). The tumor-specific reduction in relative VDR mRNA levels were 20%, 32%, and 58%, respectively.

Based on the histopathological examination, the enlarged parathyroid glands of secondary HPT were subgrouped into hyperplasias of the nodular (n = 13 glands) or diffuse (n = 10 glands) type (6). No significant difference in glandular weight could be detected between them, although the nodular type was numerically heavier (621 ± 1.30 mg vs. 460 ± 1.25 mg, P = 0.34). The nodular type was associated with a greater reduction in the relative VDR mRNA level (0.046 ± 0.003) than for the diffuse type of secondary hyperplasia (0.078 ± 0.009, P < 0.005). Linear regression analysis substantiated no relationships between VDR mRNA levels and serum PTH, serum calcium, or glandular weight in the patients with secondary HPT (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Decreased VDR protein expression seems to be a characteristic pathogenic mechanism in secondary HPT of uremia (6, 7), whereas the studies on primary HPT have been conflicting (8, 9). Herein, the VDR mRNA expression was found to be substantially reduced in parathyroid adenomas of sporadic primary HPT. This reduction seemed to be tumor-specific and not secondary to, for instance, biochemical derangements associated with the hyperparathyroid state, because there was a significant reduction in VDR gene expression in the parathyroid adenomas as compared with matched normal parathyroid glands within the same patients. The findings are in agreement with studies on VDR gene polymorphisms, which support that VDR b, a, and T alleles are associated with low VDR mRNA expression, decreased calcium-mediated control of the PTH secretion, and a disposition to develop primary HPT (10, 11, 12, 13, 14). Recently, the VDR-FokI polymorphism, which causes different lengths of the VDR, was studied in postmenopausal patients with primary HPT (18). This polymorphism was found to be weakly associated with the development of the disease and failed to correlate to VDR mRNA levels in 42 parathyroid adenomas (15). The possible importance of reduced parathyroid VDR mRNA expression in primary HPT is also strengthened by the notions on an inverse relation between the VDR mRNA levels in parathyroid adenomas and the extent of hypercalcemia in primary HPT (14).

The magnitude of the VDR mRNA reduction was similar in the enlarged parathyroid glands of primary and secondary HPT. It is unlikely that this reduction relates to inactivating mutations in the VDR gene, since no such mutations have been detected by detailed analysis of 26 parathyroid adenomas of primary HPT and 64 hyperplasias of advanced secondary HPT (19, 20). Recent studies on transgenic mice underline the importance of the VDR in the development of HPT. The HPT of VDR-ablated mice, however, can be ameliorated by a diet enriched in calcium and phosphorous (21, 22). Moreover, it has been shown that both calcium and 1,25(OH)2D3 can up-regulate VDR under normal circumstances (23, 24). The decreased VDR expression in particularly the diffuse type of hyperplasia of secondary HPT may relate to the deficient levels of circulating 1,25(OH)2D3 and calcium. This contrasts to the situation in primary HPT of Western countries. The hypercalcemia of these patients generally is accompanied by serum 1,25(OH)2D3 levels within or above the upper part of the normal range due to maintained renal effect of the relative PTH excess (25). There exists, however, an inverse relationship between serum 1,25(OH)2D3 levels and parathyroid gland mass in primary HPT (26, 27). Studies also have indicated that reduced action of the 1,25(OH)2D3-VDR complex on the parathyroid gland may predispose to primary HPT and influence clinical expression of the disease (8, 26, 27, 28). These findings indicate that the calcitriol-VDR complex may act as a risk factor, as well as a promoter, in the formation and progression of parathyroid adenomas.

Increased parathyroid cell proliferation and decreased calcium-mediated control of the PTH secretion are characteristic findings in all types of HPT. Calcium via its receptor, the CaR (28, 29), and the 1,25(OH)2D3-VDR complex are the most important regulators, in this respect. Decreased actions of these regulators would stimulate the parathyroid cells to proliferate in a polyclonal manner and hypothetically be more susceptible to somatic genetic hits (30). Parathyroid adenomas have substantiated derangements in genes thought to be involved primarily in the regulation of parathyroid growth, such as the PRAD/Cyclin D1 oncogene, and the MEN1 tumor suppressor gene (30, 31, 32, 33, 34). Monoclonality seems to be characteristic of such adenomas and a majority (>60%) of the enlarged parathyroid glands of secondary HPT (35). During the earlier phases of secondary HPT, the parathyroid cells possibly proliferate in a polyclonal manner due mainly to the deficient 1,25(OH)2D3 and calcium levels (36). Consistent with the proposed model of tumorigenesis of primary HPT, such cells might be more susceptible to genetic hits, whereby monoclonal tumors would be most likely to occur at more advanced stages of secondary HPT (30, 35). The reduction in VDR gene expression in primary HPT and in secondary HPT with a nodular type of hyperplasia may depend on mechanisms related to the monoclonal parathyroid cell proliferation rather than to actions secondary to changes in circulating variables like calcium, PTH, phosphorous, and 1,25(OH)2D3.

1,25(OH)2D3 has been shown to up-regulate the CaR in rat parathyroid cells (37). Impaired CaR mRNA and protein expression is found in parathyroid lesions of both primary and secondary HPT (38, 39), and mutations in the CaR gene have not been found in parathyroid neoplasias (40, 41). These derangements are similar to the present findings on VDR mRNA levels and concur with studies on the apparent lack of VDR gene mutations in HPT (19, 20). Despite that the mechanisms for reduced VDR and CaR expressions in parathyroid lesions is unknown, one may speculate that they act synergistic in the development of both primary and secondary HPT.


   Footnotes
 
1 Supported by the Swedish Medical Research Council, the Swedish Cancer Society, and the Swedish Society for Medical Research. Back

Received June 10, 1999.

Revised January 18, 2000.

Accepted February 7, 2000.


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 Materials and Methods
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U. Segersten, P. Correa, M. Hewison, P. Hellman, H. Dralle, T. Carling, G. Akerstrom, and G. Westin
25-Hydroxyvitamin D3-1{alpha}-Hydroxylase Expression in Normal and Pathological Parathyroid Glands
J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2967 - 2972.
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D. Sudhaker Rao and A. M. Parfitt
Vitamin D Receptor Status in Parathyroid Adenomas
J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 2328 - 2328.
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T. Carling
Vitamin D Levels and Primary Hyperparathyroidism
J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 2328a - 2328.
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