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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-0564
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 10 4152-4157
Copyright © 2008 by The Endocrine Society

BRIEF REPORT

Type I Membrane Klotho Expression Is Decreased and Inversely Correlated to Serum Calcium in Primary Hyperparathyroidism

Peyman Björklund1, Tijana Krajisnik1, Göran Åkerström, Gunnar Westin and Tobias E. Larsson

Departments of Surgical Sciences (P.B., G.Å., G.W.) and Medical Sciences (T.K., T.E.L.), Uppsala University Hospital, Uppsala University, 75185 Uppsala, Sweden

Address all correspondence and requests for reprints to: Tobias E. Larsson, M.D., Ph.D., Department of Medical Sciences, Uppsala University Hospital, Ing.70, 3 tr, UAS, 75185 Uppsala, Sweden. E-mail: tobias.larsson{at}medsci.uu.se.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: The type I membrane protein Klotho was recently shown to mediate PTH secretion in parathyroid cells in response to low extracellular calcium. In contrast, Klotho inhibits PTH secretion indirectly through the action of fibroblast growth factor-23. Abnormal Klotho expression in parathyroid disorders remains to be elucidated.

Objective: The aim of the study was to determine: 1) Klotho expression in parathyroid adenomas from patients with primary hyperparathyroidism (pHPT) compared to normal tissue; and 2) its relation to the serum calcium and PTH levels.

Design: Surgically removed parathyroid glands (n = 40) and four normal parathyroid tissue specimens were analyzed for Klotho mRNA and protein levels by quantitative real-time PCR and immunohistochemistry. In vitro effects of calcium on Klotho mRNA expression were studied in bovine parathyroid cells.

Results: Klotho mRNA levels were significantly decreased (n = 23) or undetectable (n = 17) in parathyroid adenomas compared to normal tissues (P < 0.001). Reduced Klotho protein expression was confirmed by immunohistochemistry. Klotho mRNA levels were inversely correlated to serum calcium (r = –0.97; P < 0.0001), and calcium dose-dependently decreased Klotho mRNA expression in normal parathyroid cells in vitro (P < 0.01). Serum calcium was the only significant marker of Klotho expression in multivariate analysis with calcium, phosphate, PTH, and adenoma weight as independent variables.

Conclusions: Parathyroid Klotho expression is decreased or undetectable in pHPT. We provide evidence that 1) serum calcium is strongly associated with parathyroid Klotho expression in pHPT; and 2) abnormal PTH secretion in hypercalcemic pHPT subjects is mediated by Klotho-independent mechanisms.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
The type I membrane protein Klotho encompasses 1012 amino acids with a large extracellular domain and a short cytoplasmic portion (1). Klotho is highly expressed in tissues that require abundant calcium transport, such as parathyroid glands, kidneys, and choroid plexus (1, 2, 3). Although Klotho was initially identified as a gene involved in premature aging (1), subsequent studies revealed that Klotho plays a key role in maintaining calcium homeostasis (1, 4).

Klotho regulates serum calcium concentration directly at the level of the kidney and indirectly in parathyroid glands. At low serum calcium concentrations, Klotho hydrolyzes extracellular sugar residues on the renal transepithelial calcium channel TRPV5, entrapping the channel in the plasma membrane (5). This leads to durable calcium channel activity, an increased tubular reabsorption of calcium in the kidneys and a reciprocal increase in serum calcium. Similarly, at low extracellular calcium levels, Klotho may recruit Na+/K+-ATPases to the plasma membrane of parathyroid chief cells, generating a transmembrane voltage gradient that mediates PTH secretion (4) and in turn a rise in serum calcium. Consequently, modulation of Klotho expression in physiology and pathophysiological states may have a profound impact on regulation of calcium homeostasis.

Klotho has also been demonstrated to function as a fibroblast growth factor (FGF) receptor (FGFR) cofactor for the phosphaturic hormone FGF23 (2). This is evidenced by the phenotypic similarities between Klotho and Fgf23 null mice, including shortened life span, hypercalcemia and hyperphosphatemia, elevated 1,25-dihydroxyvitamin D3, and ectopic soft-tissue calcifications (1, 6, 7). Furthermore, Klotho null mice show extremely high levels of serum Fgf23, although still harboring the Fgf23 null phenotype (2).

Due to the presence of Klotho in parathyroid glands, it was postulated that FGF23 may also modulate PTH expression. Indeed, we and others recently demonstrated that FGF23 directly decreases PTH mRNA and protein levels in vitro and in vivo (8, 9). Thus, Klotho appears to exert a dual effect on PTH secretion: direct stimulation through recruitment of Na+/K+ -ATPases (4), and indirect suppression through the FGF23 signaling pathway (8, 9).

Despite a central role of Klotho in calcium homeostasis, altered Klotho expression in parathyroid disorders remains unexplored. In this study, we further investigated parathyroid Klotho expression in a large number of adenomas of primary hyperparathyroidism (pHPT). Because pHPT is a disorder in which PTH secretion is abnormally elevated despite increased serum calcium levels, we could investigate Klotho expression in relation to uncontrolled PTH secretion and within a wide range of serum calcium levels.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patient description and tumor/normal tissue preparation

Parathyroid adenomas (n = 40; age range, 14–90 yr) were acquired from pHPT patients diagnosed and surgically treated in the clinical routine at Uppsala University Hospital during 2005–2007 (Table 1Go). Inclusion criteria were abnormal elevation of PTH in relation to serum calcium, normal creatinine levels, and no history of familial hyperparathyroidism. Patients were not treated with vitamin D or any calcimimetics. Normal parathyroid tissue (n = 4) was obtained from glands inadvertently removed in conjunction with thyroid surgery where autotransplantation was not required, or as normal parathyroid gland biopsies in patients subjected to parathyroidectomy. Tissues were intraoperatively snap-frozen as well as embedded in paraffin. Informed consent and approval by institutional ethical committee at Uppsala University were obtained (approval number 00-128).


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  		TABLE 1. Patient characteristics

 
Bovine parathyroid cells

The protocol for isolation and culturing of bovine parathyroid cells has previously been described (9). Twenty-four hours after outgrowth of cells, treatment with various concentrations of calcium was initiated. Cells were harvested after an additional 24 h and subjected to RNA extraction.

RNA extraction and cDNA synthesis

Total RNA was extracted with TriZol Reagent (Life Technologies, Inc., Gaithersburg, MD) according to the manufacturer’s instructions, and the DNA-free RNA was prepared using the NucleoSpin RNA II kit (Macherey-Nagel GmbH & Co. KG, Düren, Germany). Successful DNase treatments were verified by PCR analysis of all RNA preparations. Reverse transcription was performed with hexamer random primers using the First-Strand cDNA Synthesis Kit (Amersham Pharmacia Biotech, Uppsala, Sweden) according to the manufacturer’s instructions.

Quantitative real-time PCR analysis

Reaction conditions have previously been described in detail (9). The iQ SYBR Green Supermix (Bio-Rad, Hercules, CA) was used in all reactions, and the iCycler, MyiQ Single Color Real-Time PCR Detection System (Bio-Rad) was used for expression analysis. All samples were amplified in duplicate, and nontemplate controls were included. To confirm specificity of primers, gel electrophoresis of the PCR products revealed one distinct band for each transcript. In accordance, temperature-dependent dissociation curves for all PCR products revealed one single/identical top for each corresponding transcript. Finally, sequence analysis confirmed analysis of correct transcripts. Primers were designed by Primer3 Input at http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi and synthesized by CyberGene AB (CyberGene, Huddinge, Sweden). Primer sequences were as follows: Klotho (GenBank accession no. NC_000013): forward, 5'-tacggagacctccccatgta-3'; reverse, 5'-ccatccagtatgtgggcttt-3'; and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (GenBank accession no. NM_002046): forward, 5'-ccaccatggagaaggctggggctca-3'; reverse, 5'-atcacgccacagtttcccggagggg-3'. Standard curves for Klotho and GAPDH were established by amplifying serial dilutions of the fragments. Each sample's mean threshold value was corrected for the corresponding mean value for GAPDH, used as internal control.

Immunohistochemistry

To evaluate Klotho protein expression, we performed immunohistochemistry on frozen sections of 40 parathyroid adenomas and four normal parathyroid tissue specimens according to standard protocols. For Klotho, an anti-Klotho polyclonal goat antibody was used as primary antibody (Santa Cruz Biotechnology Inc., Santa Cruz, CA; catalog no. sc-22220). Paraffin sections were used in all stainings for proliferating cell nuclear antigen (PCNA), vitamin D receptor (VDR), and FGFR1c. All primary antibodies were purchased from Santa Cruz Biotechnology: sc-56 for PCNA, sc-1008 for VDR, and sc-7945 for FGFR1c (Flg).

Statistical analysis

Differences between Klotho-expressing vs. nonexpressing tumors were analyzed by Student’s unpaired t test. The Spearman's nonparametric model was used in the correlation analysis. Adenomas with undetectable Klotho mRNA levels (measured by real-time PCR) were arbitrarily assigned a relative Klotho value equal to 0.5. Values are presented as arithmetical mean ± SEM, unless stated otherwise. A P value of less than 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
To determine relative Klotho mRNA levels, we performed quantitative real-time PCR on cDNA obtained from 40 parathyroid adenomas and four normal parathyroid tissue specimens. Clinical data of the pHPT patients included in the study are shown in Table 1Go. Klotho mRNA levels were markedly reduced in all adenomas except for one (Klotho mRNA level within the range of the normal controls), compared with the normal tissues (30.4 ± 4.2 and 95.9 ± 7.0, respectively; P < 0.0001) (Fig. 1AGo).


Figure 1
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  		FIG. 1. A, Relative Klotho mRNA expression was measured by real-time PCR and corrected for GAPDH levels in 40 pHPT patients and four normal parathyroid tissue specimens. Parathyroid Klotho mRNA levels were significantly decreased in pHPT compared with normal tissues (mean ± SEM, 30.4 ± 4.2 and 95.9 ± 7.0; P < 0.0001). B, Decreased parathyroid Klotho expression was confirmed at the protein level by immunohistochemistry on frozen sections counterstained with Mayer's hematoxylin. Preincubation with a blocking peptide disrupted the signal, indicating specificity of the primary anti-Klotho antibody. Magnification, x20.

 
We also examined Klotho expression at the protein level by immunohistochemistry. In agreement, Klotho protein expression was decreased in all adenomas with detectable Klotho mRNA level (except for the adenoma expressing normal Klotho mRNA level) compared with the normal tissues. Representative stainings are shown in Fig. 1BGo. Peptide blocking of the anti-Klotho antibody disrupted the signal, confirming specificity (Fig. 1BGo).

In 17 adenomas, Klotho mRNA was undetectable by real-time PCR. Adenomas with undetectable Klotho mRNA level showed no immunoreactivity (data not shown), indicating concordant expression of Klotho mRNA and protein levels. Notably, all patients with undetectable tumor Klotho mRNA levels had serum calcium above 11.80 mg/dl (2.95 mmol/liter), ranging from 12.28–14.4 mg/dl (3.06–3.60 mmol/liter), suggesting a critical upper limit in serum calcium required for complete suppression of Klotho mRNA expression. Serum calcium and PTH levels were significantly increased in tumors with undetectable Klotho mRNA levels compared with Klotho-expressing tumors (P < 0.0001) (Fig. 2Go, A and B). In contrast, no significant difference in adenoma weight was found in Klotho-expressing vs. -nonexpressing tumors (Fig. 2CGo).


Figure 2
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  		FIG. 2. A, Serum calcium levels were significantly higher in Klotho-nonexpressing adenomas than in those tumors expressing Klotho. ***, P < 0.001. B, Serum PTH was significantly higher in Klotho-nonexpressing adenomas compared with Klotho-expressing tumors. ***, P < 0.001. C, The difference in adenoma weight between the two tumor groups was insignificant. Bars indicate mean ± SEM. NS, Not significant.

 
Previous studies revealed that low extracellular calcium is a stimulus for Klotho-mediated PTH secretion (4). We therefore explored the relation between serum calcium and Klotho levels. Importantly, Klotho mRNA was strongly and inversely correlated to the serum calcium level (r = –0.97; P < 0.0001) (Fig. 3AGo), whereas no correlation was found between Klotho mRNA level and serum PTH (Fig. 3BGo). Finally, there was no correlation between Klotho mRNA level and adenoma weight or serum phosphate (data not shown). We further analyzed the association between calcium and Klotho, applying a multivariate linear regression analysis with Klotho as the dependent variable and serum calcium, PTH, phosphate, and adenoma weight as independent variables. Importantly, calcium was the only variable independently associated with Klotho (Table 2Go).


Figure 3
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  		FIG. 3. A, Klotho mRNA levels in pHPT were inversely and significantly correlated to serum calcium (r = –0.97; P < 0.0001) in a Spearman's nonparametric correlation model. Note that 17 subjects with serum calcium above 11.80 mg/dl (2.95 mmol/liter) had undetectable Klotho mRNA levels. These were arbitrarily assigned a relative Klotho/GAPDH mRNA value of 0.5. B, No significant association was found between Klotho mRNA and serum PTH levels.

 

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  		TABLE 2. Multivariate linear regression analysis with Klotho as the dependent variable

 
The strong correlation between serum calcium and Klotho level suggested a direct Klotho regulation by calcium. To explore such a possibility, we used an in vitro model of primary isolated bovine parathyroid cells, in which calcium dose-dependently decreased Klotho mRNA level (P < 0.01) (Fig. 4Go).


Figure 4
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  		FIG. 4. Calcium dose-dependently decreased Klotho mRNA expression in bovine parathyroid cells in vitro at 24 h in the concentration range 3–4 mmol/liter, supporting the in vivo observation that Klotho is gradually suppressed in pHPT with increasing serum calcium levels. **, P < 0.01; ***, P < 0.001.

 
To exclude the possibility that the Klotho down-regulation is due to adenoma cell proliferation, we determined the expression level of the proliferation marker PCNA by immunohistochemistry (Fig. 5Go). All adenomas, regardless of serum calcium levels, had a high but similar amount of proliferating cells (Fig. 5Go); thus, no significant association between Klotho levels and adenoma cell proliferation was observed. Because proliferating parathyroid cells are associated with a decrease in VDR expression in pHPT (10, 11, 12), we also investigated expression levels of VDR and FGF23/Klotho FGFR1c (2) proteins. Similarly, no difference was observed in levels of VDR or FGFR1c between high-calcium- vs. low-calcium-derived adenomas (Fig. 5Go), indicating that reduced or absent Klotho expression in pHPT is independent of expressional changes in VDR or FGFR1c.


Figure 5
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  		FIG. 5. Immunohistochemical detection on paraffin sections of the proliferation marker PCNA (top), the VDR (middle), and the FGFR1c (bottom) proteins in adenomas derived from pHPT patients. Representative stainings are shown for patients that had calcium levels within the highest range (left) vs. the lowest range (right). No significant difference in the expression of these markers was observed over various serum calcium concentrations, supporting the hypothesis that decreased Klotho expression in pHPT is independent of proliferation and/or expressional changes in VDR and the Klotho/FGF23 receptor FGFR1c. All sections except the PCNA stainings were counterstained with Mayer's hematoxylin. Magnification, x10.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In this study, we demonstrate that Klotho mRNA and protein expression is decreased or undetectable in parathyroid adenomas from pHPT subjects and that parathyroid Klotho expression in pHPT is closely correlated to the serum calcium level.

Reduced parathyroid Klotho expression in pHPT may have several causes. One possibility is that serum calcium directly suppresses parathyroid Klotho expression, supported by a dose-dependent decrease in Klotho mRNA level by calcium treatment of parathyroid cells in vitro. Furthermore, all subjects with serum calcium higher than 11.80 mg/dl (2.95 mmol/liter) had undetectable Klotho levels, indicating that severe hypercalcemia completely suppresses Klotho expression.

Decreased Klotho expression in pHPT tumors is highly relevant because a recent study by Imura et al. (4) demonstrated that Klotho mediates PTH secretion in a calcium-dependent manner through recruitment of the Na+/K+-ATPase to the plasma membrane. Thus, there may be two separate mechanisms for PTH secretion: one including a conventional (Klotho-independent) pathway, and another including Klotho recruitment of Na+/K+-ATPase (4).

Speculatively, the Klotho-dependent mechanisms for PTH secretion may be more important in states of hypocalcemia. In this regard, Klotho may serve as a "rescue" hormone, protecting the body against hypocalcemia through additional enhancement of PTH secretion, although future studies are needed to explore such a possibility.

On the other hand, the conventional pathway may play a more important role for PTH secretion in states of hypercalcemia. This is supported by our present findings in pHPT, showing high PTH secretion in the setting of hypercalcemia and low/undetectable Klotho levels, which points toward Klotho-independent mechanisms for sustained PTH secretion. To test such a hypothesis, it would be of interest to determine parathyroid Klotho expression in other hypercalcemic states, for example metastasis-induced hypercalcemia.

Another aspect of the current study is the fact that Klotho is a permissive FGFR cofactor for FGF23 (2, 13). Although circulating levels of FGF23 and PTH often are paralleled, especially in patients with chronic kidney disease (14), recent data indicate that FGF23 exerts a negative feedback on parathyroid glands, suppressing PTH mRNA and protein secretion (8, 9). Thus, it is possible that diminished Klotho expression in pHPT abrogates the protective effect of FGF23 on PTH secretion.

Along the same line, the mild elevation of FGF23 commonly observed in pHPT (in the face of hypophosphatemia) (15, 16), may also be a physiological attempt to increase FGF23 signaling despite insufficient amounts of Klotho. In support, we found a nearly 2-fold increase in PTH levels in the Klotho-nonexpressing tumors compared with Klotho-expressing tumors, which possibly reflects absence of FGF23 inhibition of PTH secretion in the Klotho nonexpressing tumors. It would have been further enlightening to determine serum FGF23 in our pHPT study subjects; however, remaining serum samples are not available. Further studies are required to elucidate the impact of FGF23 signaling on PTH secretion in states of reduced Klotho expression.

It is not clear whether reduced Klotho expression plays a role in the pathogenesis of pHPT, or whether it is only secondary to biochemical changes such as hypercalcemia. In support for a role of Klotho in tumorigenesis, Klotho was demonstrated to directly inhibit several Wnt ligands, thus antagonizing the Wnt signaling pathway (17). Intriguingly, deregulated activation of the Wnt/β-catenin signaling pathway in hyperparathyroid tumors has been reported recently. The accumulation of β-catenin was caused by expression of an internally truncated lipoprotein receptor-related protein 5 receptor or by stabilizing mutation in β-catenin (18, 19). Stabilizing mutation in β-catenin occurred at low frequency (20).

Finally, as a note of caution, it should be emphasized that our data were obtained in the context of a pathological condition in which normal regulatory mechanisms for PTH (and possibly Klotho expression) are deranged and may not be valid in physiology. Thus, we cannot exclude the possibility that the parathyroid calcium-Klotho axis behaves differently in normal physiology or in other states of abnormal calcium homeostasis than pHPT where no primary defect(s) in the parathyroid glands are present.

In conclusion, parathyroid Klotho expression is decreased and inversely correlated to serum calcium in pHPT. Our findings provide novel insights into the regulatory mechanisms of Klotho expression and abnormal PTH secretion in pHPT.


   Acknowledgments
 
We thank Birgitta Bondeson for valuable technical assistance.


   Footnotes
 
This work was supported by the Swedish Research Council, the Novo Nordisk Foundation, the Swedish Kidney Foundation, and the Swedish Society of Medicine.

Disclosure Statement: The authors have nothing to declare.

First Published Online August 5, 2008

1 These authors contributed equally to this work. Back

Abbreviations: FGF, Fibroblast growth factor; FGFR, FGF receptor; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; PCNA, proliferating cell nuclear antigen; pHPT, primary hyperparathyroidism; VDR, vitamin D receptor.

Received March 11, 2008.

Accepted July 29, 2008.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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