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7 Roles of the Calcium-Sensing Receptor and the Vitamin D Receptor in the Pathophysiology of Secondary Hyperparathyroidism

7 Roles of the Calcium-Sensing Receptor and the Vitamin D Receptor in the Pathophysiology of Secondary Hyperparathyroidism

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M.E. Rodríguez-Ortiz et al.



Fig. 7.3 Schematic view of the pathophysiology of secondary hyperparathyroidism. GFR glomerular filtration rate, 1,25(OH)2D3 calcitriol, P phosphorus, Ca calcium, PTH parathyroid

hormone



Uremic patients develop progressive parathyroid hyperplasia as a consequence

of a maintained stimulation of parathyroid function. It is accepted that the progression of parathyroid hyperplasia is enhanced by the decrease in the serum

concentrations of 1,25(OH)2D3, the tendency to hypocalcemia and the rise in serum

P levels. However, the exact mechanisms that drive parathyroid cells to proliferate

are not clear. It is generally accepted that low 1,25(OH)2D3 contributes to the development of parathyroid hyperplasia [38]. 1,25(OH)2D3 is a primary inhibitor of parathyroid cell proliferation by acting on the gene expression of the cell cycle regulator

c-myc [39]. In vitro and in vivo studies [39–41] indicate that 1,25(OH)2D3 suppress

parathyroid hyperplasia.

During the early stages of SHPT, parathyroid growth is polyclonal, giving rise to

diffuse hyperplasia (Fig. 7.4). However, at some time point during the late stage in

the evolution of SHPT, there is a transformation from diffuse to nodular hyperplasia

as a result of monoclonal growth of parathyroid cells. Studies performed in vitro

using parathyroid tissue from uremic patients that had required parathyroidectomy

demonstrate that in nodular hyperplasia there is blunted response to the inhibitory

effect of both Ca [43] and 1,25(OH)2D3 [44]; this is explained by a reduced expression of VDR and CaR [45, 46]. Fukuda et al. [8] firstly showed a lower density of

VDR in nodular than in diffuse human parathyroid hyperplasia; similar findings were



7 Vitamin D and Parathyroid Hormone Regulation in Chronic Kidney Disease



157



Fig. 7.4 Progression of parathyroid hyperplasia in chronic kidney disease (Adapted from Komaba

et al. [42])



reported by Tokumoto et al. [47]. Gogusev et al. [37] showed that CaR is reduced in

nodular hyperplasia. This explains, at least in part, the poor control of parathyroid

cell proliferation by vitamin D and Ca in patients with markedly advanced SHPT,

which is characterized by parathyroid nodular hyperplasia [44]. In parathyroid cells

the regulation of activation of the CaR induces the incorporation of CaR to the cell

membrane, which results in amplification of the inhibitory signal [21].

Whether the decrease in VDR and CaR occurs at the onset of parathyroid hyperplasia or the reduced expression is a consequence of cell proliferation is controversial. Taniguchi et al. [48] reported that in five-sixth nephrectomized rats on a high P

diet (HPD) there was a reduction of parathyroid VDR expression and a simultaneous elevation in p21 (marker of cell proliferation) as early as day 1, while the

increase in cell proliferation rate was first observed on day 3. These results suggest

that down-regulation of VDR and the elevation of p21 may play a key role in the

pathogenesis of SHPT. However, in normal rats the increase in cell proliferation

induced by a high phosphorus diet (HPD) was observed on day 1 and preceded a

transient down-regulation of VDR expression first observed on day 5; by contrast,

an increase in cell proliferation was not seen until day 5 in a low Ca diet (LCD) rats,

and coincided with the transient down-regulation of VDR expression. In this experiment, the expression of CaR was no affected by either diet [49].



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A number of factors have been suggested to contribute to the down-regulation of

VDR in the hyperplasic parathyroid tissue. Firstly, the reduced levels of 1,25(OH)2D3

would prevent the homologous up-regulation of its own receptor. Secondly, as

serum Ca has been also established as a key regulator of VDR expression, the hypocalcemia related to SHPT might also contribute to the reduced expression of parathyroid VDR in secondary hyperparathyroidism. Finally, uremic toxins may also

reduce the stability of VDR mRNA and then, decrease the expression of VDR protein [50].



7.8



Conclusion



The presence of the vitamin D receptor and the calcium-sensing receptor in parathyroid chief cells enables the parathyroid gland to respond to vitamin D and calcium,

two of the main regulators of the parathyroid function.

Calcium and vitamin D have both independent and cooperative effects on parathyroid function inhibition. Besides modulating its own receptor, vitamin D also

regulates the calcium-sensing receptor, which makes parathyroid gland more sensitive to the suppressive action of calcium. Vitamin D upregulates vitamin D receptor

only if calcium is normal or high. Conversely, vitamin D receptor is downregulated

in hypocalcemia and upregulated by activation of the calcium-sensing receptor.

Inhibition of parathyroid function by Vitamin D is impaired in the presence of

hypocalcemia

In chronic kidney disease, the prolonged stimulation of parathyroid glands promotes parathyroid hyperplasia. If treatment is not applied, severe secondary hyperparathyroidism develops, that may become resistant to medical treatment; such is

the case of nodular hyperplasia of the parathyroids. Hyperplasia is accompanied by

a decrease in the expression of parathyroid receptors, including FGFR-1 and klotho.

Although the exact mechanisms whereby parathyroid hyperplasia is developed are

not completely understood, several factors such as the hypocalcemia, the phosphorus retention and the deficiency in vitamin D has been directly associated to an

increase in cell proliferation.



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Chapter 8



The Parathyroid Type I Receptor and Vitamin

D in Chronic Kidney Disease

Pablo A. Ureña Torres, Jordi Bover, Pieter Evenepoel, Vincent Brandenburg,

Audrey Rousseaud, and Franck Oury



Abstract Parathyroid hormone (PTH) regulates mineral and bone metabolism

through its specific type I receptor (PTH1R). In the kidney, PTH inhibits proximal

tubular reabsorption of phosphate, stimulates the synthesis of 1,25(OH)2D3, and

enhances calcium reabsorption in the thick ascending limb of Henle’s loop. In the

skeleton, the physiological action of PTH is more complex. PTH has a paradoxical

anabolic/catabolic effect and combines the simultaneous modulation of resorption

and formation of bone tissue, and ultimately of bone remodeling rate. This paradoxical anabolic/catabolic effect relies on its mode of administration. Intermittent

or pulsatile PTH has a bone anabolic effect, while chronic administration or excessive production of PTH, as in case of primary and secondary hyperparathyroidism,

is detrimental for the skeleton due to stimulation of bone resorption. The PTH1R is

an 84-kDa glycosylated protein that belongs to the seven transmembrane domains

G protein-coupled receptors family. It activates two intracellular signaling pathways, protein kinase A and phospholipase C, through the stimulation of Gs and Gq

proteins. The differential use of one or another of these two signaling pathways



P.A. Ureña Torres, MD, PhD (*)

Ramsay-Générale de Santé, Service de Néphrologie et Dialyse, Clinique du Landy,

Saint Ouen, France

Department of Renal Physiology, Necker Hospital, University of Paris V, René Descartes,

Paris, France

e-mail: urena.pablo@wanadoo.fr

J. Bover, MD, PhD

Department of Nephrology, Fundaciò Puigvert, IIB Sant Pau, REDinREN, Barcelona, Spain

P. Evenepoel, MD

Division of Nephrology, Dialysis and Renal Transplantation, Department of Medicine,

University Hospital Leuven, Leuven, Belgium

V. Brandenburg

Department of Cardiology and Center for Rare Diseases (ZSEA), RWTH University Hospital

Aachen, Aachen, Germany

A. Rousseaud • F. Oury, MD

Institut National de la Santé et de la Recherche Médicale (INSERM) U115, Institut Necker

Enfants Malades (INEM), Université Paris Descartes, Paris, France

© Springer International Publishing Switzerland 2016

P.A. Ureña Torres et al. (eds.), Vitamin D in Chronic Kidney Disease,

DOI 10.1007/978-3-319-32507-1_8



163



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depends on the connection of PTH1R with the sodium-dependent hydrogen

exchanger regulatory factor-1 (NHERF-1). In early chronic kidney disease (CKD),

PTH1R is down-regulated in bone and kidney, which may favor the development of

secondary hyperparathyroidism and CKD-mineral and bone disorders (CKDMBD). In contrast, vitamin D deficiency is able to up-regulate renal and skeletal

PTH1R in subjects with normal renal function. However, daily and intermittent

administration of active vitamin D inhibits PTH1R expression and function in bone

cells. This chapter reviews basic and clinical data regarding PTH1R and its physiological actions, as well as resistance to PTH hypercalcemic action and PTH1R

implications in CKD-MBD.

Keywords CKD-MBD • Calcium • Phosphate • PTH • Bone • Cholecalciferol

• Adynamic bone disease • Fracture



8.1



Introduction



The parathyroid hormone (PTH) is a polypeptide produced by the chief cells of the

parathyroid glands and stored in secretory granules. Many years ago, PTH was

identified as one of the major regulators of the calcium (Ca2+)/phosphate homeostasis in vertebrates, with bone and kidney as the main target organs [1, 2]. In the kidney level, PTH has three major physiological functions which are essential for the

maintenance of the (Ca2+)/phosphate homeostasis. First, PTH stimulates calcium

reabsorption in the thick ascending limb of Henle’s loop [2, 3]. Second, it inhibits

proximal tubular reabsorption of phosphate in blocking sodium-dependent phosphate co-transport by reducing the amount of the Npt2a and Npt2c proteins on the

cell surface [4–6]. Third, PTH will also promote the synthesis of active vitamin D

(1,25(OH)2D3 or calcitriol), that will enhance calcium and phosphate absorption by

the intestine. In the bone, PTH leads to the release of calcium and phosphate.

However, the physiological actions of PTH on bone metabolism are more complex

and only partially understood. PTH has a paradoxical anabolic/catabolic effect that

relies on its mode of administration. Excessive production of PTH observed in primary hyperparathyroidism or chronic administration of PTH leads to an increase in

bone resorption by modulating osteoclast number and activity. In contrast, intermittent administration or pulsatile secretion of PTH leads to an increase of bone formation [7, 8].

In turn, Ca2+ is the most important regulator of circulating PTH levels. Via its

binding to- and the activation of the calcium sensing receptor (CaSR) in the chief

cells of the parathyroid glands, Ca2+ modulates PTH secretion and biosynthesis,

PTH gene expression and parathyroid cellular proliferation. Indeed, hypocalcemia

will induce, while hypercalcemia will decrease PTH secretion.

In mammals, PTH functions are mediated by two known receptors that belong

to the G protein-coupled receptor family: PTH1R and PTH2R. PTH1R is the clas-



8 The Parathyroid Type I Receptor and Vitamin D in Chronic Kidney Disease



165



sical PTH receptor involved in regulating mineral ion homeostasis and playing an

essential role in the clinical and biological manifestations of the secondary hyperparathyroidism (SHPT) observed in chronic kidney disease (CKD). In addition to

PTH, PTH1R possesses also the property to bind the paracrine factor PTHrP (parathyroid hormone-related protein) with nearly equal affinity [1, 9]. In contrast, PTHrelated functions of the second receptor, PTH2R, are less known. Moreover,

PTH2R does not recognize PTHrP but presents a high affinity profile to another

ligand, the neuropeptide tuberoinfundibular peptide of 39 amino acid residues

(Tip39) [10].

In this chapter will review the basic and clinical data regarding PTH1R and its

physiological actions, as well as resistance to PTH, hypercalcemic action and

PTH1R implications in CKD-MBD.



8.2



Parathyroid Related Peptide



PTHrP was initially identified in the course of investigating the cause of tumors

associated with humoral hypercalcemia of malignancy [11]. The human PTHrP

gene is a complex transcriptional unit located on chromosome 3 (3p21.1–p24.2).

Importantly, PTH and PTHrP evolve presumably from a common ancestry precursor after gene duplication event in the beginning of vertebrate diversification [12].

What remains from this common heritage is a limited region of amino acid sequence

homology in the N terminus regions, a feature that enable these two molecules to

bind and activate a common receptor, PTH1R, a member of the G-protein coupled

receptor family B.

In contrast to PTH, which is only physiologically produced by the parathyroid

glands, PTHrP is made in various tissues, both at embryonic and adult stages.

Indeed, although initially discovered in malignancies, PTHrP is expressed in a large

variety of other organs, such as the kidney, bone, central nervous system, endocrine

pancreas, fetal parathyroid glands or placenta, where it can modulate cell growth

and differentiation in an autocrine/paracrine [13–16].

Numerous studies have clearly documented the indispensable biological importance of PTHrP/PTH1R signaling which is involved in: (i) the regulation of smooth

muscle cells contraction and relaxation, namely in the bladder, uterus, intestine and

vessels [17, 18]; (ii) the trans-epithelial mineral ion transport in the mammary

glands, placenta and kidney [19]; (iii) the skeletal fetal development, in particular,

endochondral bone ossification [20]; and (iv) the control of the epithelial/mesenchymal interaction in the skin and the mammary glands. In vitro studies have also

shown that PTHrP displays other functions largely relating to intracrine signaling

in the nucleus/nucleolus [21–23]. Some tumors, including epidermal, renal and

urothelial tumors, go along with excessive PTHrP production, which may spill over

to the circulation and extent distant PTH-like effects such as increased calcium

bone release, underlying the phenomenon of malignancy hypercalcemia [17,

24–26].



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8.3



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Tuberoinfundibular Peptide 39



Tuberoinfundibular peptide 39 (TIP39) is a 39-amino acid molecule member of the

PTH and PTHrP family of peptide hormones that exerts its function by interacting,

at least in part, with the PTH type 2 receptor (PTH2R). TIP39 is mainly expressed

in the hypothalamus and in other distinct areas of the central nervous system. Recent

studies suggested that the interaction between PIT39 and PTH2R in the brain modulate the regulatory network of nociception and response to the fear (16–17).

Importantly, TIP39 and PTH2R are also expressed in other tissues, including testis,

seminiferous tubules, liver, kidney and chondrocytes, suggesting that it might have

other physiological actions. For instance and as expected, in chondrocyte cells

TIP39 is an efficient PTH2R activator whereas it is a potent antagonist of the

PTH1R. In such way that TIP39/PTH2R signaling inhibits cell proliferation and

alters differentiation of chondrocytes through the modulation of SOX9 gene expression [27]. Circulating TIP39 is measurable and its concentration has been associated

with functional parameters and fertilizing capacity of spermatozoa in animals [28],

however, to the best of our knowledge there is no clinical data reporting serum

TIP39 levels in CKD nor if TIP39/PTH2R are modulated by vitamin D.



8.4



Biochemical and Functional Characteristics

of the PTH1R



PTH and PTHrP can bind and activates the PTH receptor type I (PTH1R) with the

same affinity. The PTH1R is an 84-kDa glycosylated protein, which belong to the

large family of G protein-coupled receptors also known as seven transmembrane

domain receptors. After binding to its receptor, PTH stimulates one of the G proteins, in the occurrence, the Gs protein (composed of three subunits α, β and γ),

which activates adenylate cyclase and increases intracellular cAMP in target cells

[1, 9]. PTH is also capable of increasing intracellular free calcium concentration by

at least three mechanisms: (1) firstly by stimulating phospholipase C (PLC)/diacylglycerol/inositide-triphosphate pathway and activating protein kinase C (PKC)

[29]. The coupling between PTH1R and PLC is ensured by the protein Gq; (2)

secondly, by stimulating the release of stored ionized calcium from intracellular

compartments independently of the activation of PLC; and (3) thirdly, by stimulating an inward calcium flux through the activation of calcium channels [2, 3, 30].

The differential use and activation of one or another intracellular signaling pathways by PTH depends on the connection of PTH1R with the adaptative and regulatory protein NHERF-1 (sodium-dependent hydrogen exchanger regulatory factor-1)

[31]. In case of activation of the PKC signaling pathway by PTH, NHERF-1 is the

only protein allowing the interaction between PTH1R and PLCβ. This implies that

the presence or the absence of NHERF-1 in a given cell type will determine the intracellular signaling pathway chosen by PTH to exert its specific biological action [31].



8 The Parathyroid Type I Receptor and Vitamin D in Chronic Kidney Disease



167



The PTH1R may also require another important adapter protein, Dvl

(Dishevelled), which is implicated in the complex formed by frizzled receptor/

LRP5-6 (low-density lipoprotein-related protein) and the activation of the Wnt

(Wingless)/beta-catenin signaling pathway in bone cells. Indeed, the binding of

PTH to PTH1R activates beta-catenin pathway by directly recruiting Dvl, independent of Wnt or LRP5-6, and thereby modulates osteoblast differentiation and osteoclastogenesis [32].

PTH acts on bone by inducing the phosphorylation of its receCptor PTH1R and

activates both the protein kinase A (PKA) and Wnt pathways [33]. PTH also

increases FGF23 mRNA levels through both the PKA and Wnt pathways [34].

Activation of PKA by the activated PTH1R increases the orphan nuclear receptor

Nurr1 mRNA levels to induce FGF23 transcription [35, 36].

The cloning of the PTH1R in 1992 provided essential insights regarding its

molecular structure [1, 9]. The gene is located on chromosome 11 and contains at

least 15 exon-coding regions, which give rise to an amino acid sequence with seven

putative transmembrane domains, and several conserved cysteine residues that are

required for the receptor function and where the receptor can be glycosylated. Three

promoters have been identified on the PTH1R gene, which might be selectively

utilized in distinct organs such as kidney and bone [37]. The PTH1R belongs to the

class II subgroup of G protein-coupled receptor family together with the receptors

for calcitonin, secretin, glucagon, glucagon-like peptide (GLP), gastric inhibitor

peptide (GIP), pituitary adenylate cyclase-activating peptide (PACAP), and vasointestinal peptide (VIP). The PTH1R cloning also allowed to definitively answer three

historical questions: (1) the PTH receptor expressed in the kidney and in bone cells

was the same one; (2) the PTH1R was capable of activating the two intracellular

signaling pathways already known to be stimulated by PTH; and (3) PTH and

PTHrP bind with the same affinity and activate with the same potency the

PTH1R. Finally, the identification of the PTH1R demonstrated that this receptor

plays a crucial role in endochondral bone development and growth.



8.5



Specific Features of PTH1R



PTH1R was the first receptor identified for PTH, which also indistinctly recognizes

PTHrP [1, 9]. A second receptor was then identified and called PTHR2 because of

its amino acids similarity with PTH1R. This receptor binds to TIP39 and PTH, but

does not recognize PTHrP [38]. PTHR2 is mainly expressed in the brain and in

somatostatin-producing cells in pancreatic islets, and does not appear to participate

in mineral and bone metabolism as PTH does [39]. Its human gene is located on

chromosome 2 (2q33) [40]. A third nucleotide sequence has been identified, which

has a great similarity with the two other PTH receptors [41]. This receptor is present in zebrafish, seabream, and chicken and shows a stronger affinity for PTHrP

than for other members of the PTH receptors family [42–44], however, this receptor has not yet been identified in human. There are also biochemical and functional



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