Regulation of parathyroid hormone gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat.

Naveh-Many, Tally; Silver, Justin

doi:10.1172/jci114840

Cited by 205 publications

(93 citation statements)

References 26 publications

(23 reference statements)

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“…These approaches were proven successful in our study because calcium and phosphorus blood levels were maintained normal, and PTH levels were also maintained normal. The dose of calcitriol was pharmacologic, and thus direct suppression of PTH gene transcription (54,55) may have been an important component of maintaining normal PTH levels.…”

Section: Discussionmentioning

confidence: 99%

Successful Treatment of an Adynamic Bone Disorder with Bone Morphogenetic Protein-7 in a Renal Ablation Model

Lund¹,

Davies²,

Brown³

et al. 2004

Journal of the American Society of Nephrology

103

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Abstract. An adynamic bone disorder (ABD) is an important complication of chronic kidney disease (CKD) of unknown etiology for which there is no adequate treatment. Reported is an animal model of ablative CKD complicated by an ABD characterized by the absence of secondary hyperparathyroidism and its successful treatment with a skeletal anabolic factor, bone morphogenetic protein-7 (BMP-7). Adult mice were subjected to electrocautery of the right kidney followed by left nephrectomy. Animals were randomized into groups fed normal chow or fed low-phosphate chow supplemented with calcitriol to maintain normophosphatemia in CKD. All groups were maintained on the regimens for 12 wk. Hyperphosphatemia, secondary hyperparathyroidism, and a mild osteodystrophy developed in the CKD/chow-fed group, as expected. When dietary phosphorus was restricted and calcitriol was administered in the CKD low-phosphate/calcitriol group (ABD), Ca, PO 4 , and parathyroid hormone levels were maintained normal. A significant ABD developed in the ABD group characterized by significant depressions in osteoblast number, perimeters, bone formation rates, and mineral apposition rates when compared with the sham-operated, chow-fed group. The abnormal skeletal histomorphometry was reversed by BMP-7 therapy to normal values and significantly improved from the ABD group (P Ͻ 0.05). The sham-operated low-phosphate/ calcitriol-fed control group and the CKD low-phosphate/calcitriol/BMP-7 groups had reduced phosphate levels compared with the other groups (P Ͻ 0.05). ABD produced in mice with CKD in the absence of hyperparathyroidism was successfully reversed with a bone anabolic, BMP-7, associated with a reduction in plasma phosphorus.Renal osteodystrophy is a term used to describe a heterogeneous spectrum of skeletal abnormalities found in patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD). Renal osteodystrophy ranges from states of high bone turnover to states of low bone turnover (1-3). Predominantly hyperparathyroid bone disease results in a high turnover osteodystrophy (osteitis fibrosa), and it is considered the most prevalent bone disorder in chronic kidney disease and ESKD. Low-turnover osteodystrophy reflects the lack of capacity to produce and mineralize bone matrix and has two main histologic forms: osteomalacia and the adynamic bone disorder (ABD). The ABD is an important complication of CKD associated with high rates of bone fractures (4), impaired growth (5,6), and probably vascular calcification (7,8). There has been an increase in the prevalence of ABD in patients with ESKD on dialysis (9).The pathogenesis of the ABD is unknown. It may occur when parathyroid hormone (PTH) levels are aggressively suppressed (10). As a result, practice standards target maintaining elevated intact PTH levels (about three to five times normal) sufficient to prevent the ABD (11,12). Therapy of the ABD besides adjustment of PTH levels is not available. Because secondary hyperparathyroidism in CKD causes a distinct osteodystrophy, in...

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Section: Discussionmentioning

confidence: 99%

Successful Treatment of an Adynamic Bone Disorder with Bone Morphogenetic Protein-7 in a Renal Ablation Model

Lund¹,

Davies²,

Brown³

et al. 2004

Journal of the American Society of Nephrology

103

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“…These results suggest that the downregulation of VDR by hypocalcemia resulted in impairment of the inhibitory action of CTR on parathyroid cell function. Other authors (5,7) have shown that the inhibition of PTHmRNA by CTR is relatively ineffective when serum Ca concentration is low. This finding could be related to the low VDR expression induced by low Ca.…”

Section: Discussionmentioning

confidence: 99%

“…Because CTR decreases parathyroid gene transcription of PTHmRNA, additional experiments were performed to evaluate whether the decrease in VDR expression induced by hypocalcemia prevented the normal downregulation of PTHm-RNA by CTR (5). Thus a bolus of CTR was administered to rats before induction of hypocalcemia while other rats received the bolus after 6 h of hypocalcemia (when VDR was already downregulated by hypocalcemia).…”

Section: Discussionmentioning

confidence: 99%

“…A study by Naveh-Many et al (5) showed that the ability of exogenous CTR to inhibit PTHmRNA in vitamin D-deficient rats was markedly impaired when serum Ca was low, suggesting that the inhibition of PTHmRNA by CTR was not possible if hypocalcemia was present. In a more recent publication, Sela-Brown et al (6) have shown that a decrease in Ca produces an increase in the expression of calreticulin, a cytoplasmic protein that prevents the binding of vitamin D receptorretinoid X receptor-␤ to the PTH vitamin D response element (VDRE).…”

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confidence: 99%

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Regulation of Parathyroid Vitamin D Receptor Expression by Extracellular Calcium

Garfia¹,

Cañadillas²,

Canalejo

et al. 2002

Journal of the American Society of Nephrology

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Abstract. Low extracellular calcium (Ca) stimulates parathyroid hormone (PTH) secretion and also increases the renal synthesis of calcitriol (CTR), which is known to decrease PTH production. This study began with the hypothesis that the parathyroid cell response to CTR may be modulated by extracellular Ca concentration through an effect on parathyroid cell vitamin D receptor (VDR). In the present study, rat parathyroid glands were incubated in low (0.6 mM) and high (1.5 mM) Ca concentration. The parathyroid VDRmRNA was higher in 1.5 than 0.6 mM Ca. Furthermore, this effect was not observed in incubated slices of kidney cortex and medulla, tissues which also possess both Ca and vitamin D receptors. Experiments were also performed to evaluate the effect of Ca on VDR expression in vivo. Male Wistar rats received intraperitoneal injections of CaCl 2 or a single intramuscular injection of EDTA to obtain 6 h of hypercalcemic (ionized Ca, 1.4 to 1.6 mM) or hypocalcemic (ionized Ca, 0.85 to 0.95 mM) clamp; a third group of rats was used as control. A small dose of CTR was administered to hypercalcemic rats to match the serum CTR levels of hypocalcemic rats. Parathyroid gland VDRm-RNA and VDR protein were increased in hypercalcemic rats as compared with hypocalcemic rats. Increasing doses of CTR upregulated VDRmRNA and VDR only in hypercalcemic rats. Additional experiments showed that the decrease in VDR in hypocalcemic rats prevented the inhibitory effect of CTR on PTHmRNA. In conclusion, our study shows that extracellular Ca regulates VDR expression by parathyroid cells independently of CTR and that by this mechanism hypocalcemia may prevent the feedback of CTR on the parathyroids.The parathyroid cell increases parathyroid hormone (PTH) secretion in response to a decrease in the extracellular calcium (Ca) concentration. A cell membrane Ca sensor receptor enables these cells to respond to small changes in serum Ca concentration (1). PTH acts on its target organs, mainly kidney and bone, to increase the serum Ca to its normal level. Calcitriol (CTR), the production of which is stimulated by hypocalcemia and also by PTH, is another hormone that contributes to restoration of normocalcemia by stimulating intestinal absorption of Ca (2). Thus there are two different hormones, PTH and CTR, with a calcemic effect, and both share the commitment of preserving normocalcemia. The elevation of serum Ca feeds back on the parathyroid cell, inhibiting PTH secretion and synthesis (2); in addition, high CTR also inhibits PTH synthesis by acting on specific vitamin D receptors (VDR) (3). The inhibitory effect of CTR on parathyroid cells has been widely demonstrated to the point that CTR is used to reduce PTH levels in uremic patients with advanced hyperparathyroidism (4). However, it would not seem appropriate that CTR should inhibit PTH synthesis if hypocalcemia persists; such inhibition would counteract the function of the parathyroid cell, which is to restore normocalcemia. Furthermore, it would seem paradoxical that the parathyroid c...

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“…Activation of the an extracellular calcium sensing receptor (CaSR) when [Ca 2ϩ ] e concentrations are high maintains the storage form of PTH in the parathyroid gland (3,4). Release of PTH from the parathyroid gland is a direct result of a decrease in serum [Ca 2ϩ ] e (5,6). PTH is a potent stimulus of 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) biosynthesis in the kidney proximal convoluted tubule by its induction of 1␣-hydoxylation (7).…”

Section: Extracellular Ionized Calcium [Ca 2ϩmentioning

confidence: 99%

Extracellular Calcium-sensing Receptor Activation Induces Vitamin D Receptor Levels in Proximal Kidney HK-2G Cells by a Mechanism That Requires Phosphorylation of p38α MAPK

Maiti

Hait

Beckman

2008

Journal of Biological Chemistry

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2؉ ] e concentration in the physiological range is capable of directly increasing renal proximal VDR expression, and the induction mechanism requires activation of the CaSR and signal mediation by the p38␣ MAP kinase pathway.Extracellular ionized calcium [Ca 2ϩ ] e is a critical mediator of cell signaling for the storage and release of both parathyroid hormone (PTH) 2 and calcitonin. Homeostasis of [Ca 2ϩ ] e is important to proper neuromuscular contractions, cellular integrity, and the deposition of mineral in skeletal structures (1). A multi-organ system coordinates and maintains [Ca 2ϩ ] e homeostasis within a narrow physiological range (2). Activation of the an extracellular calcium sensing receptor (CaSR) when [Ca 2ϩ ] e concentrations are high maintains the storage form of PTH in the parathyroid gland (3,4). Release of PTH from the parathyroid gland is a direct result of a decrease in serum [Ca 2ϩ ] e (5, 6). PTH is a potent stimulus of 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) biosynthesis in the kidney proximal convoluted tubule by its induction of 1␣-hydoxylation (7). Resultant increase in [Ca 2ϩ ] e by 1,25(OH) 2 D 3 regulates PTH at two levels; where CaSR signaling shuts down PTH secretion (8, 9) and 1,25(OH) 2 D 3 through transactivation of its nuclear receptor (VDR) inhibits prepro-PTH transcription (10).[Ca 2ϩ ] e is also a potent mediator of the balance between cellular proliferation and differentiation while VDR mediates biological functions of 1,25(OH) 2 D 3 and is expressed in many different cell types (11). Past work has focused on the role of VDR in mineral homeostasis, with VDR activators used mainly to treat hyperparathyroidism secondary to chronic kidney disease (12). A more recent perspective includes the use of vitamin D analogs in combination with calcimimetics and phosphate binders in the management of hyperparathyroid disorders (13). It is therefore important to identify the mechanisms whereby CaSR signaling and VDR activation coincide in the tissues that co-express these two receptors. We previously reported for the first time that [Ca 2ϩ ] e is a direct regulator of VDR in proximal human kidney . The present study was designed to better explore the mechanism by which [Ca 2ϩ ] e influences VDR increase in these cells.PTH exerts several actions in the renal proximal tubule that include control of phosphate transport and induction of 1,25(OH) 2 D 3 -1␣-hydroxylase (CYP27B1) mRNA (15-17). The receptor for PTH is a another member of the GPCR family capable of coordinating bidirectional signaling through pathways involving adenylate cyclase or activation of protein kinase C depending on the concentration of PTH and the specific cell type (18,19). In proximal tubule epithelial cells, PTH stimulates 1␣-hydroxylation, mediates 1,25(OH) 2 D 3 -24-hydroxylase (CYP24) down-regulation and represses 1,25(OH) 2 D 3 -receptor (VDR) transcription all by increasing cAMP and activating the cAMP-dependent response element-binding protein (CREB) (20 -22). However, the set of ...

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Regulation of parathyroid hormone gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat.

Cited by 205 publications

References 26 publications

Successful Treatment of an Adynamic Bone Disorder with Bone Morphogenetic Protein-7 in a Renal Ablation Model

Successful Treatment of an Adynamic Bone Disorder with Bone Morphogenetic Protein-7 in a Renal Ablation Model

Regulation of Parathyroid Vitamin D Receptor Expression by Extracellular Calcium

Extracellular Calcium-sensing Receptor Activation Induces Vitamin D Receptor Levels in Proximal Kidney HK-2G Cells by a Mechanism That Requires Phosphorylation of p38α MAPK

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