The Regulation of Parathyroid Hormone Secretion and Synthesis

Home , Parathyroid chief cell, Parathyroid gland

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Rajiv Kumar* and James R. Thompson†

*Division of Nephrology and Hypertension, Department of Internal Medicine, Biochemistry and Molecular Biology, and †Department of Physiology, Biophysics and Bioengineering, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota

ABSTRACT Secondary hyperparathyroidism classically appears during the course of chronic renal basis of these observations regarding failure and sometimes after renal transplantation. Understanding the mechanisms by pathogenesis, therapy for 2°HPT in the which parathyroid hormone (PTH) synthesis and secretion are normally regulated is context of CKD and ESRD includes the important in devising methods to regulate overactivity and hyperplasia of the para- control of serum phosphate concentra- ϩ thyroid gland after the onset of renal insufficiency. Rapid regulation of PTH secretion tions, the administration of Ca2 and in response to variations in serum calcium is mediated by G-protein coupled, calcium- vitamin D analogs, and the administra- sensing receptors on parathyroid cells, whereas alterations in the stability of mRNA- tion of calcimimetics.33,34,16,35,36 encoding PTH by mRNA-binding proteins occur in response to prolonged changes in Nevertheless, 2°HPT remains a signifi- serum calcium. Independent of changes in intestinal calcium absorption and serum cant clinical problem and additional meth- calcium, 1␣,25-dihydroxyvitamin D also represses the transcription of PTH by associ- ods for the treatment of this condition would ating with the vitamin D receptor, which heterodimerizes with retinoic acid X receptors be helpful, especially in refractory situations, to bind vitamin D-response elements within the PTH gene. 1␣,25-Dihydroxyvitamin D where other measures have failed or are only additionally regulates the expression of calcium-sensing receptors to indirectly alter partially effective. Knowledge about the mec- PTH secretion. In 2°HPT seen in renal failure, reduced concentrations of calcium- hanisms by which parathyroid hormone se- sensing and vitamin D receptors, and altered mRNA-binding protein activities within cretion and synthesis occur is therefore of the parathyroid cell, increase PTH secretion in addition to the more widely recognized value in designing new approaches to the changes in serum calcium, phosphorus, and 1␣,25-dihydroxyvitamin D. The treatment treatment of this condition. Here we briefly of secondary hyperparathyroidism by correction of serum calcium and phosphorus review the mechanisms that modulate PTH concentrations and the administration of vitamin D analogs and calcimimetic agents release and secretion and identify abnormal- may be augmented in the future by agents that alter the stability of mRNA-encoding ities that are present in progressive renal dis- PTH. ease.

J Am Soc Nephrol 22: ●●●–●●●, 2011. doi: 10.1681/ASN.2010020186 PTH RELEASE AND SYNTHESIS DETERMINE SERUM PTH The central role of the parathyroid creased incidence of fractures and mor- CONCENTRATIONS ϩ glands in regulating Ca2 homeostasis tality.13–16 by modulating bone metabolism, the The pathogenesis of 2°HPT in CKD is Serum PTH concentrations are depen- synthesis of 1␣,25-dihydroxyvitamin complex. Phosphate retention, hyperphos- dent upon the release of PTH stored in ␣ 2ϩ 2ϩ D(1 ,25(OH)2D) in proximal tubules, phatemia, low serum Ca (sCa ), elevated 2ϩ and the reabsorption of Ca in the levels of parathyroid hormone (PTH), Published online ahead of print. Publication date ␣ 2ϩ distal nephron is widely appreciated by 1 ,25(OH)2D deficiency, intestinal Ca available at www.jasn.org. 1–5 the readers of this journal. Second- malabsorption, the reduction of vitamin D Correspondence: Dr. Rajiv Kumar, Division of Ne- ary hyperparathyroidism (2°HPT) fre- receptors (VDR) and calcium-sensing recep- phrology and Hypertension, Departments of Medi- quently occurs in the setting of chronic tors (CaSR) in the parathyroid glands, and cine, Biochemistry and Molecular Biology, Mayo Clinic and Foundation, 200 1st Street SW, Roches- kidney disease (CKD), of end-stage re- altered mRNA-binding protein activities ter, MN 55905. Phone: 507-284-0020; Fax: 507-538- nal disease (ESRD), or after renal trans- modulating PTH transcripts play a role in the 9536; E-mail: [email protected] 6–12 17–30 plantation, and uncontrolled 2°HPT development of 2°HPT. Parathyroid hy- Copyright © ●●●● by the American Society of in CKD and ESRD associates with an in- perplasia is often present as well.31,32 On the Nephrology

J Am Soc Nephrol 22: ●●●–●●●, 2011 ISSN : 1046-6673/2202-●●● 1 BRIEF REVIEW www.jasn.org secretory granules within the parathyroid gland and by the synthesis of new ϩ PTH.1,37 sCa2 , phosphorus, and vitamin D metabolites play a role in regulating PTH release and synthesis.1,3,28,38–41 Rapid PTH release from secretory granules in hypocalcemic states is modulated by the binding of Ca2ϩ to CaSRs on chief cells, Figure 1. A hypothetical dimeric model of residues D23 (blue) to I528 (red) of the human whereas long-term replenishment of PTH calcium sensing receptor extracellular domain (CaSR ECD). (A) Both monomers contain- stores is dependent on new PTH synthesis ing just the Venus flytrap region of the CaSR ECD are shown in a closed and presumably that is controlled by the availability of active conformation as was reported for the extracellular domain of the glutamate mRNA-encoding PTH for ribosomal trans- receptor with glutamate bound. The two yellow spheres (yellow arrows) indicate putative ϩ lation into prepro-PTH.2,42,43,27,44–49 Hy- Ca2 -binding sites, found at the nexus of where both lobes of a monomer meet. Most pocalcemia also retards the rate of degrada- residues forming this cation-binding site are not conserved in glutamate receptor. The tion of PTH within the parathyroid gland, additional cyan spheres within the topmost lobes of the dimer designate possible 2ϩ thus making more PTH available for re- Mg -binding sites (green spheres indicated by green arrows) brought over from gluta- 2ϩ lease,50,51 and increases cell division in the mate receptor coordinates. These Mg sites are completely conserved in CaSR. The parathyroid gland possibly through the ac- dimer interface of the portion of CaSR shown is completely formed from interactions between these two upper lobes. There are no intermolecular disulfide bridges linking the tion of the CaSR.1,42,45,52 Phosphorus addi- dimer together within this portion of the ECD of CaSR, although two intramolecular tionally alters PTH synthesis, although the disulfides exist. (B) A model of the apo-CaSR dimer is portrayed. Again, the color ramps ϩ precise mechanisms by which changes in from blue to red from D23 to I528. The Mg2 sites are present, although there is no phosphate concentrations are detected experimental basis for this premise. Of note is the significant opening and expansion or sensed by the parathyroid gland are of the cavities between the upper and lower lobes of each monomer, the areas unknown.28 1␣,25-Dihydroxyvitamin indicated by the two yellow ovals. (C) The upper lobes of the CaSR atomic coordi- ␣ 2ϩ D(1 ,25(OH)2D) alters the transcrip- nates shown above in (A) (with Ca bound, now made gray in color) are superim- tion of PTH and may have an indirect posed on the apo-form model for the CaSR dimer drawn in rainbow as in (B). The red effect on PTH release by increasing the arrows point to a large displacement in the orientation and position of the carboxy- expression of CaSR.38–41,45,53–56 terminal end of the structure near where the CaSR cysteine-rich domains (not shown) might be found. Significant conformational changes within parts of the CaSR ECD connecting with the transmembrane domains probably occur on Ca binding. ROLE OF THE CASR IN MEDIATING PTH RELEASE meostasis is demonstrated by the bio- 1ewk)78 as the template for main chain logic consequences of inactivating or atoms. The atomic coordinates within Changes in concentrations of sCa2ϩ are activating mutations of the receptor. the model were inspected and manually sensed by chief cells through a cell-sur- Inactivating mutations of the CaSR result corrected for steric clashes, for alterna- face, seven-transmembrane, G protein– in familial benign hypercalcemia or neona- tive residue rotamer choices that im- coupled receptor, the CaSR,42,57–59 and tal severe hyperparathyroidism, whereas prove hydrogen bonding, and for Ram- receptor activity results in rapid alter- activating mutations result in autosomal achandran and other conformational ations in PTH secretion.37 After the in- dominant hypocalcemia.62,63,53,64–68 outliers. The CaSR dimer from D23 to duction of abrupt and sustained hy- The CaSR has a large extracellular do- I528 displays perfect twofold symmetry pocalcemia, plasma concentrations of main of approximately 600 amino acids, similar to that of the glutamate receptor PTH increase within 1 minute, peak at 4 a seven-pass transmembrane domain, bound with both glutamate and gadolin- ϩ to 10 minutes, and thereafter decline and an intracellular carboxyl-terminal ium ions.79 The putative Ca2 -binding gradually to approximately 60% of the domain that has several phosphorylation sites were included in our CaSR model ϩ ϩ maximum at 60 minutes, despite ongo- sites.69 The receptor binds Ca2 in its ex- based on the presence of Gd2 atomic ing and constant hypocalcemia. Abrupt tracellular domain, most likely as a dimer coordinates within other glutamate re- restoration of normocalcemia from the in the so-called “Venus flytrap” configu- ceptor structures (PDBs 1ewk and 1isr). ϩ hypocalcemic state causes levels of PTH ration (Figure 1, A through C).70–73 Our In the glutamate receptor, the Gd2 lo- to decrease with an apparent half-life of model of the human CaSR shown in Fig- cation occurs at an acidic patch, includ- approximately 3 minutes. In addition to ure 1 was obtained using multiple se- ing the ligating residues E238, D215, and its role in the parathyroid gland, the quence alignments and initial coordinate E224 with one standout residue R220. CaSR plays an important role in regulat- models and two separate algorithms.74–77 The acidic residues of equivalent posi- ing Ca2ϩ reabsorption in the thick as- The best model resulted from using the tions in CaSR are conserved, although an cending limb of the loop of Henle.60–62 extracellular domain of the glutamate arginine residue is not conserved. There- The vital role of the CaSR in Ca2ϩ ho- receptor (Protein Data Bank code fore, it is likely that the Ca2ϩ-binding po-

2 Journal of the American Society of Nephrology J Am Soc Nephrol 22: ●●●–●●●, 2011 www.jasn.org BRIEF REVIEW sition in the glutamate receptor and the substances (“calcimimetic” agents) po- vate signaling pathways that regulate cel- CaSR are similar. tentiate the CaSR to subthreshold con- lular growth through MAPKs, ERKs, and ϩ ϩ When Ca2 binds to the CaSR, it elic- centrations of Ca2 . Several synthetic JNK kinases.96–100 The binding of CaSRs its a conformational change within the CaSR modulators have been developed to intracellular scaffolding proteins such extracellular domain of the receptor for the treatment of hyperparathyroid- as filamin A is important in mediating (compare Figure 1B with Figure 1C). ism. NPS-R-467 and NPS-R-568 (phe- this effect.97,101–108 The CaSR interacts These changes are possibly transmitted nylalkylamines) are examples of alloste- with filamin A to create a scaffold neces- through the seven-pass transmembrane ric activators of the CaSR. Cinacalcet sary for the organization of Gq␣, Rho domain to allow interactions of the intra- (Sensipar) is an example of a calcimi- guanine nucleotide exchange factor, and cellular domains of the receptor with metic phenylalkylamine used to reduce Rho signaling pathways.55 The affinity of heterotrimeric G protein subunits, Gqa PTH secretion that is now increasingly the CaSR for filamin A is greater in the ϩ ϩ 2 2 104 and Gia. In addition to Ca , the CaSR used in the treatment of 2°HPT in renal presence of Ca . Filamin A protects binds several metals, amino acids, antibi- disease and in primary hyperparathy- the CaSR from degradation,104 and si- otics, and organic compounds that mod- roidism.90–92 Other compounds, known lencing filamin A expression with siR- ulate its activity (Figure 2).80–85 For as “calcilytic” agents, block the CaSR and NAs inhibits CaSR signaling.101 CaSR modeling of phenylalanine and neomy- allow the release of increased amounts of activation increases the activity of a se- cin, coordinates were docked into our PTH from the parathyroid gland for any rum-response element by increasing the ϩ model of CaSR manually, maximizing given sCa2 concentration.83,93–95 These membrane localization of the Rho pro- the number of hydrogen bonds while agents, when administered intermit- tein.55 minimizing the number of steric clashes. tently, could be useful for the treatment Transcription of the CaSR is not in- 2ϩ Agents such as L-amino acids with ar- of osteoporosis.83,93–95 fluenced by Ca concentrations but is 2ϩ ␣ omatic side chains exert allosteric effects When extracellular Ca binds to the altered in vivo by 1 ,25(OH)2Dinthe on the CaSR and sensitize it to the effects CaSR, it elicits conformational changes parathyroid gland, in the kidney, and ϩ of agonists such as Ca2 .80,81,86–89 These within the receptor. The heterotrimeric in thyroid C cells.24,55,54,56 Vitamin D

G protein subunits, Gqa and Gia, are re- response elements have been identified cruited to the receptor and alter the in the two promoter regions (P1 and amounts or activity of several intracellu- P2), 380 and 160 bp upstream of the lar mediators including Ca2ϩ, cAMP, transcription start sites of the CaSR and phospholipases within the chief cell gene, respectively.55 These vitamin D ϩ (Figure 3).42,59,70 Intracellular Ca2 is al- response elements are atypical hexam- tered as a result of activation of phospho- eric repeats that are separated by three

lipase C (PLC) by the Gq␣ subunit of the nucleotides. In CKD, CaSR amounts heterotrimeric G proteins. This results in are reduced in the parathyroid gland, the PLC-mediated hydrolysis of phos- most likely as a result of hyperplasia phatidylinositol-4,5,-bisphosphate and and perhaps as a result of reduced serum ␣ 109–112 the resultant formation of inositol 1,4,5- 1 ,25(OH)2D concentrations. The re- trisphosphate and diacylglycerol. 1,4,5- ductions in CaSR concentrations in the Trisphosphate mobilizes intracellular parathyroid gland attenuate the respon- Ca2ϩ stores by binding to its cognate re- siveness of the gland to sCa2ϩ and contrib-

ceptor. The CaSR also interacts with Gi␣ ute to 2°HPT. to inhibit adenylate cyclase activity that reduces intracellular cyclic AMP.42 In ad-

Figure 2. Models of bound phenylala- dition, activation of PLA2 results in the nine and neomycin molecules within the production of arachidonic acid and acti- THE REGULATION OF PTH cavities of the CaSR dimer. (A) Above the vation of phophatidylinositol 4-kinase SYNTHESIS ϩ predicted Ca2 -binding sites shown by which replenishes phosphatidylinositol- yellow spheres are phenylalanine mole- 4,5,-bisphosphate.42,59,70 These changes As noted earlier, replenishment of PTH cules shown in a conformation that stacks within chief cells rapidly enhance the re- stores after the release of preformed PTH is its side-chain ring against a tryptophan res- lease of preformed PTH from the para- dependent on the synthesis of new prepro- idue that is unique to CaSR, whereas re- thyroid gland. PTH by ribosomes.1,2,43 This is dependent, maining atoms occupy the same locations In addition to controlling PTH re- in turn, upon the availability of mRNA- as found for the glutamate molecules 2ϩ bound to glutamate receptor. (B) Two neo- lease and modulating Ca flux in the encoding PTH. As we discuss in the sec- mycin molecules may also be docked kidney, the CaSR also plays a role in the tions that follow, changes in mRNA con- within a third buried location as shown in control of cellular differentiation, cellu- centrations are the result of changes in the bottom-most image. lar growth, and apoptosis.96 CaSRs acti- PTH gene transcription or mRNA stability.

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are less well-defined and generally do not Ca2+ contain an AUUUA sequence.125,114,122

Extra-cellular Cell As shown in Figure 4A, RNAs targeted membrane for degradation undergo deadenylation, decapping, and degradation in a large Intra-cellular multiprotein complex, the exosome, or Activation Gq Gq Gq AA in cytoplasmic compartments known as i a a of PLA 2 GW bodies or processing bodies (P-bod- 126–128 Inhibition Activation Activation ies). A 63-nucleotide ARE in the of AC of PLC of MAPK 3Ј-UTR of murine mRNA-encoding PTH, comprised of a core 26-nucleotide Decreased Formation of Formation of MEK minimal binding sequence and adjacent cAMP Ins(1,4,5)P3 DAG PtdIns(4,5)P2 flanking regions, regulates mRNA stability in response to changes in Ca2ϩ and phos- Mobilization of Activation ERK 1/2 phate concentrations.28,44,129 The ARE in intra-cellular Ca of PKC the 3Ј-UTR of mRNA-encoding PTH ϩ Figure 3. Pathways by which the CaSR homodimer signals in cells after binding of Ca2 binds two proteins, AU-rich element– to the extracellular domains (red line) of the CaSR molecules in the homodimeric pair. binding protein 1 (AUF1) and K-ho- Through the association of the CaSR with the i-type heterotrimeric G protein, Gi␣, mology splicing regulatory protein adenylate cyclase (AC) activity is inhibited and cyclic AMP (cAMP) concentrations de- (KSRP).27,29 AUF1 increases mRNA half- crease. Association of the CaSR with the Gq␣ subunit of q-type heterotrimeric G protein life, whereas KSRP has the opposite ef- results in the activation of PLC that increases inositol (1,4,5)P3 and diacylglycerol (DAG) fect.27,29 Both proteins are regulated by with attendant downstream effects such as an increase in intracellular calcium that is ϩ changes in sCa2 and phosphate and are mobilized from intracellular stores, and the activation of PKC. MAPK and PLA are 2 altered in CKD.27,30,130 activated by Gq␣-dependent pathways with increases in MEK and ERK and an increase in arachidonic acid formation. The Bioactivity of KSRP Is Altered by Other Intracellular Enzymes Transcriptional Regulation of within the 3Ј-untranslated region that Peptidyl-prolyl cis-trans isomerase, NIMA- mRNA-Encoding PTH influence mRNA stability.28,27,44,48,49 interacting-1 (Pin1), a peptidyl-prolyl iso- The rate of transcription of the PTH gene By way of background, after tran- merase,altersKSRPphosphorylationandthe ␣ 38,39,41,45 Ј is repressed by 1 ,25(OH)2D. scription, nascent RNA undergoes 5 - binding of KSRP to the AREs in mRNA-en- ␣ 1 ,25(OH)2D binds to the VDR receptor methyl capping, splicing, cleavage, and coding PTH. Pin1 binds to KSRP and pre- and the liganded VDR, in association with polyadenylation in the nucleus (Figure vents the phosphorylation of KSRP at serine the retinoic acid X receptor (RXR), binds 4A).114–117 After export from the nu- residue 181. Nonphosphorylated KSRP is ac- to a vitamin D response element within the cleus, mRNA transcripts interact with tive and enhances degradation of mRNA-en- promoter region of the PTH gene.113 Struc- RNA-binding proteins that influence coding PTH (Figure 4B). Pin1 specifically turally,thisresponseelementresemblesthose RNA half-life and stability within the cell binds serine/threonine–protein motifs and found in other genes that are upregulated by (Figure 4A).95,118–120 RNA-binding pro- catalyzes the cis-trans isomerization of pep- ␣ ␣ 1 ,25(OH)2D. Reduced 1 ,25(OH)2D con- teins interact with sequence-specific ele- tide bonds, thereby changing the activity of centrations in CKD or ESRD, as well as re- ments, adenine- and uridine-rich ele- proteins. Pin1 interacts with AUF1 and duced VDR concentrations within the para- ments (AREs), that are usually present stabilizes mRNA-encoding GMCSF and thyroid gland, contribute to 2°HPT.23 within the 3Ј-untranslated regions (3Ј- TGFB.131,132 Interestingly, Pin1 epitopes UTRs) of RNA and regulate the rate at and Pin1 enzymatic activity are detectable in Role of RNA-Binding Proteins in which mRNAs are translated or de- rat parathyroid glands and parathyroid ex- the Regulation of mRNA-Encoding graded in cells.121,114,122–124 The fate of tracts.30 In heterologous cell systems, inhibi- PTH by Changing mRNA Stability an mRNA species containing an ARE tion of Pin1 activity, or knockdown of Pin1 When sCa2ϩ concentrations decrease, bound to ARE-binding proteins is expression, increases mRNA-encoding PTH levels of mRNA-encoding PTH increase partly dependent upon the relative by inhibiting degradation, whereas overex- within the parathyroid gland.46,47 Sur- amounts of different bound stabilizing pression of Pin1 reduces mRNA-encoding prisingly, changes in mRNA synthesis in or destabilizing ARE-binding proteins. PTH by accelerating its decay. Pin1 null mice response to decreases in sCa2ϩ are not AREs have a variable structure: Class I AREs have increased levels of PTH in the parathy- due to changes in PTH gene transcrip- contain several copies of the AUUUA roid gland and circulating serum PTH con- ϩ tion.28,27,44,48,49 Rather, levels of bovine motif dispersed within U-rich regions; Class centrations without changes in sCa2 and and murine mRNA-encoding pth are II AREs possess at least two overlapping phosphate levels. regulated by proteins that bind elements UUAUUUA(U/A)nonamers;ClassIIIAREs Induction of 2°HPT by feeding rats

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A DNA Transcription

5' methyl capping

Splicing

Cleavage

E1 E2 E3 E4 Polyadenylation Nucleus

E1 E2 E3 E4

Cytoplasm Export B P AAAAAAAA Active KSRP E1 E2 E3 E4 E1 E2 E3 E4 P Cytoplasm Pin1 Inactive KSRP ARE-BP ARE-BP P AAAAAAAA AAAAAAAA E1 E2 E3 E4 E1 E2 E3 E4 AAAAAAAA Stabilization Destabilization De-adenylation Degradation AAAAAAAA E1 E2 E3 E4 AAAAAAAA AAAAAAAA

Ribosome De-capping Ribosome Exosome P-body PTH RNA translation Translation PTH RNA degradation

Exosome P-body Degradation

Figure 4. (A) Cellular processing of mRNA. Nascent mRNA comprised of exons (E1 through E4) and intervening sequences (IVS) is processed in the nucleus by 5Ј-methyl capping, splicing, cleavage, and polyadenylation. In the cytoplasm, AU-rich element– binding proteins (ARE-BPs, blue box and red oval) bind to AREs within the 3Ј-region of RNA and stabilize or destabilize mRNA. Stabilized mRNA undergoes translation in ribosomes, whereas destabilized mRNA undergoes deadenylation, decapping, and degradation in exosomes or P-bodies. (Adapted from reference 130 with permission from the American Society for Clinical Investigation.) (B) Processing of mRNA-encoding PTH. Murine mRNA-encoding PTH is bound by ARE-BPs, which either stabilize or destabilize the mRNA. The ratio of activities of stabilizing/destabilizing ARE-binding proteins bound to mRNA-encoding PTH determines the half-life of the mRNA. KSRP is a mRNA-destabilizing ARE-BP for mRNA-encoding PTH that is active in its dephosphorylated state. The peptidyl-prolyl isomerase Pin1 is responsible for the dephosphorylation of KSRP. In CKD, Pin1 activity is reduced, and as a result less dephosphorylated (active) KSRP is available. Consequently, a stabilizing ARE-BP, AUF1, is active and mRNA-encoding PTH is degraded to a lesser extent, resulting in higher intracellular mRNA levels, more PTH synthesis, and secondary hyperparathyroidism. Abbreviation: P, phosphate. (Adapted from reference 130 with permission from the American Society for Clinical Investigation.) a low Ca2ϩ diet or by inducing CKD Pin1 activity, less nonphosphorylated ity of mRNA-encoding PTH is in- with adenine reduces Pin1 activity in KSRP is available to bind to the ARE in creased because of unopposed AUF1 the parathyroid gland.30 Reduced Pin1 the 3Ј-UTR of mRNA-encoding activity. Increased amounts of mRNA activity correlates with increased levels PTH.30 The reduction in Pin1 activity allow more PTH to be synthesized in of mRNA-encoding PTH in the PT reduces the ratio of the ARE-BPs, ribosomes and hyperparathyroidism glands of rats fed a low Ca diet or rats KSRP, and AUF1. AUF1 activity pre- results. It is not known what triggers with renal failure. As a result of low dominates, and the half-life and stabil- the reduction in Pin1 activity in the

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Parathyroid chief cell advances. Annu Rev Biochem 52: 411–439, 1983

Systemic factors Ca2+ 5. Gesek FA, Friedman PA: On the mecha- –Reduced SCa nism of parathyroid hormone stimulation of –Increased SPi CaSR; reduced amounts calcium uptake by mouse distal convoluted –Reduced 1α, 25(OH) D in PTG in CRF/ESRD 2 tubule cells. J Clin Invest 90: 749–758, 1992 VDR reduced 6. Isakova T, Gutierrez O, Shah A, Castaldo L, in CRF/ESRD Holmes J, Lee H, Wolf M: Postprandial RXR PTH gene Increased expression VDR in CRF/ESRD mineral metabolism and secondary hyper- or (reduced repression) parathyroidism in early CKD. JAmSoc Nucleus CaSR gene Reduced expression Nephrol 19: 615–623, 2008 in CRF/ESRD PTH mRNA 7. Moranne O, Froissart M, Rossert J, Gauci C, Boffa JJ, Haymann JP, M’Rad MB, Jac- P quot C, Houillier P, Stengel B, Fouqueray AAAAAAAA Active KSRP E1 E2 E3 E4 B: Timing of onset of CKD-related meta- P Stabilization Pin1 bolic complications. J Am Soc Nephrol 20: destabilization Inactive KSRP 164–171, 2009 P Altered RNA 8. Potts JT, Reita RE, Deftos LJ, Kaye MB, AAAAAAAA processing Richardson JA, Buckle RM, Aurbach GD: AAAAAAAA Degradation Secondary hyperparathyroidism in chronic Ribosome renal disease. Arch Intern Med 124: 408– PTH RNA translation 412, 1969 Exosome P-body 9. Johnson WJ, Goldsmith RS, Arnaud CD: PTH RNA degradation Prevention and treatment of progressive secondary hyperparathyroidism in ad- vanced renal failure. Med Clin North Am Cell membrane 56: 961–975, 1972 10. Kumar R: Renal osteodystrophy: A complex disorder. J Lab Clin Med 93: 895–898, Figure 5. Alterations within the parathyroid gland that favor the development of 2°HPT 1979 in the context of CRF and ESRD. 11. Bricker NS, Slatopolsky E, Reiss E, Avioli LV: Caclium, phosphorus, and bone in renal disease and transplantation. Arch Intern 2ϩ parathyroids in CKD and Ca defi- for the control of secondary hyper- Med 123: 543–553, 1969 ciency. parathyroidism and parathyroid hy- 12. Reiss E, Canterbury JM, Kanter A: Circulat- perplasia. Such drugs might be used in ing parathyroid hormone concentration in conjunction with vitamin D analogs chronic renal insufficiency. Arch Intern Med 124: 417–422, 1969 CONCLUSIONS and calcimimetic agents for the treat- 13. Danese MD, Kim J, Doan QV, Dylan M, ment of 2°HPT. Griffiths R, Chertow GM: PTH and the risks Thus, in CKD and ESRD, multiple ab- for hip, vertebral, and pelvic fractures normalities contribute to the develop- Disclosures among patients on dialysis. Am J Kidney ment of 2°HPT by enhancing the rate Dr. Kumar’s laboratory is supported by NIH Dis 47: 149–156, 2006 14. Jadoul M, Albert JM, Akiba T, Akizawa T, of PTH release and synthesis (Figure 5). grants DK76829 and DK77669, and grants Arab L, Bragg-Gresham JL, Mason N, Prutz These factors include a reduction in from Genzyme (GRIP) and Abbott. KG, Young EW, Pisoni RL: Incidence and number of CaSRs in the parathyroid risk factors for hip or other bone fractures gland, and a reduction in the number of among hemodialysis patients in the Dialy- sis Outcomes and Practice Patterns Study. VDRs, which influence the transcription DISCLOSURES Kidney Int 70: 1358–1366, 2006 of CaSR and PTH. In addition, there are None. 15. Rudser KD, de Boer IH, Dooley A, Young B, changes in the amounts of mRNA- Kestenbaum B: Fracture risk after parathy- encoding PTH binding proteins, spe- roidectomy among chronic hemodialysis pa- cifically those that increase mRNA deg- tients. J Am Soc Nephrol 18: 2401–2407, REFERENCES radation and that favor an increase in 2007 16. Block GA, Klassen PS, Lazarus JM, Ofsthun levels of mRNA-encoding PTH within 1. Habener JF, Rosenblatt M, Potts JT Jr.: N, Lowrie EG, Chertow GM: Mineral me- the chief cell. Modulators of CaSR and Parathyroid hormone: Biochemical aspects tabolism, mortality, and morbidity in main- VDR already are available and are in of biosynthesis, secretion, action, and me- tenance hemodialysis. J Am Soc Nephrol widespread use for the treatment of tabolism. Physiol Rev 64: 985–1053, 1984 15: 2208–2218, 2004 2°HPT in CKD and ESRD. The devel- 2. Potts JT: Parathyroid hormone: Past and 17. Slatopolsky E, Bricker NS: The role of phosphorus restriction in the prevention of sec- opment of parathyroid gland specific present. J Endocrinol 187: 311–325, 2005 3. Kumar R: Metabolism of 1,25-dihydroxyvi- ondary hyperparathyroidism in chronic re- modulators of ARE-binding proteins tamin D3. Physiol Rev 64: 478–504, 1984 nal disease. Kidney Int 4: 141–145, 1973 might result in drugs that are effective 4. DeLuca HF, Schnoes HK: Vitamin D: Recent 18. Slatopolsky E, Caglar S, Gradowska L, Can-

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