Dietary Phosphorus Restriction Reverses the Impaired Bone
Mineralization in Vitamin D Receptor Knockout Mice

Masuyama, Ritsuko; Nakaya, Yumi; Tanaka, Shinya; Tsurukami, Hiroshi; Nakamura, Toshio; Watanabe, Shaw; Yoshizawa, Tatsuya; Kato, Shigeaki; Suzuki, Kazuharu

doi:10.1210/endo.142.1.8050

Cited by 30 publications

(18 citation statements)

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“…55 In addition, apparent phosphate absorption in the intestine is not decreased in young Vdr-null mice. 56,57 Furthermore, as demonstrated by Segawa et al, 35 NPT2b expression is not only influenced by 1,25(OH) 2 D signaling, but it is also upregulated by dietary phosphate restriction through a 1,25(OH) 2 D-independent pathway. These data indicate that the intestinal epithelial cell is capable of responding to the luminal concentration of phosphate and controls NPT2b expression to increase phosphate transport.…”

Section: Mechanisms Of Phosphate Absorption In the Intestinementioning

confidence: 86%

Vitamin D endocrine system and the intestine

Christakos¹,

Lieben²,

Masuyama³

et al. 2014

BoneKEy Reports

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Calcium and phosphate regulate numerous biological processes and they are essential for bone mass and bone quality. The calcium and phosphate balance largely depends on intestinal absorption, and the dietary content of these ions determines the type of transport. High dietary intake of calcium and phosphate enables absorption by passive transport, but often the dietary content of these ions is in the low-normal range, especially for calcium. In this condition, the contribution of active intestinal calcium transport will increase to maintain normal serum levels. This adaptation is mainly regulated by the active form of vitamin D, 1,25 dihydroxyvitamin D, and requires normal concentrations of the precursor 25-hydroxyvitamin D. When intestinal calcium absorption is insufficient, hormonal adaptations will release calcium from bones to secure normocalcemia, not only by increasing bone loss but also by decreasing bone mineralization. These data underline the fact that adequate calcium intake is critical to secure skeletal integrity. Despite the insights that sufficient dietary calcium intake and normal 25-hydroxyvitamin D levels are critical for calcium and bone homeostasis, surprisingly little is known on the proteins that mediate intestinal calcium transport. Also, the interaction between the intestine and the kidney to control serum phosphate levels is still incompletely understood.

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Section: Mechanisms Of Phosphate Absorption In the Intestinementioning

confidence: 86%

Vitamin D endocrine system and the intestine

Christakos¹,

Lieben²,

Masuyama³

et al. 2014

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“…VDR (Ϫ/Ϫ) mice exhibit features similar to those of patients with hereditary vitamin D-resistant rickets, which results from genetic mutations in the VDR gene (25,30,31,56). VDR (Ϫ/Ϫ) mice display retarded growth, hypocalcaemia, hypophosphatemia, and severely impaired bone mineralization (25,56).…”

Section: Discussionmentioning

confidence: 99%

“…Mice [VDR (ϩ/ϩ) and VDR (Ϫ/Ϫ)] were weaned at 3 wk of age and given free access to water and a control diet containing 0.5% P i and 0.5% Ca for 6 days (30,31). On day 7, mice were assigned to one of two groups: the control P i group, which was fed a diet containing 0.5% P i, 0.5% Ca, and 20% lactose; and the low-Pi group, which was fed a diet containing 0.25% P i, 0.5% Ca, and 20% lactose (30,31).…”

Section: Methodsmentioning

confidence: 99%

“…On day 7, mice were assigned to one of two groups: the control P i group, which was fed a diet containing 0.5% P i, 0.5% Ca, and 20% lactose; and the low-Pi group, which was fed a diet containing 0.25% P i, 0.5% Ca, and 20% lactose (30,31). After 4 wk of test diet administration, mice were anesthetized with intraperitoneal pentobarbital sodium, and the tissues were rapidly removed.…”

Section: Methodsmentioning

confidence: 99%

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Intestinal Na-P_icotransporter adaptation to dietary P_icontent in vitamin D receptor null mice

Segawa¹,

Kaneko²,

Yamanaka³

et al. 2004

American Journal of Physiology-Renal Physiology

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168

132

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Recent studies suggest that vitamin D may play a role in intestinal Na(+)-dependent phosphate transport adaptation to variable levels of dietary P(i). Therefore, the goal of the current study was to assess Na(+)-dependent P(i) cotransport activity in transgenic mice to determine whether vitamin D is an essential mediator of this process. Intestinal brush-border membrane (BBM), Na(+)-dependent P(i) cotransport activity was significantly decreased in vitamin D receptor (VDR) null [VDR (-/-)] mice compared with wild-type (VDR+/+) mice. While intestinal Na-P(i) cotransporter (type IIb) mRNA levels were similar in VDR (-/-) and VDR (+/+) mice, type IIb Na-P(i) cotransporter protein expression was markedly suppressed in VDR (-/-) mice compared with VDR (+/+) mice. Furthermore, Na-P(i) cotransport activity in renal BBM was similar in VDR (-/-) and VDR (+/+) mice, but type IIa Na-P(i) cotransporter protein expression was decreased in VDR (-/-) mice. After administration of a low-P(i) diet, type IIb protein expression was significantly increased in VDR (+/+) and VDR (-/-) mice, and type IIb protein expression was present in the intestinal BBM of VDR (-/-) mice. These data demonstrate that intestinal Na-P(i) cotransport adaptation to a low-P(i) diet occurs independently of vitamin D.

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“…Each component of this combined treatment strategy addresses abnormalities responsible for the pathogenesis of hyperparathyroidism, but each has limitations due to potential undesirable side effects at doses required to effectively suppress PTH hypersecretion (3)(4)(5)(6). In this regard, treatment with vitamin D sterols is often complicated by hypercalcemia and hyperphosphatemia (7)(8)(9)(10), resulting in elevate calcium ϫ phosphorus levels, predisposition to soft tissue calcification, and increased mortality risk in the ESRD population (11)(12)(13)(14)(15).…”

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confidence: 99%

The Calcimimetic AMG 073 as a Potential Treatment for Secondary Hyperparathyroidism of End-Stage Renal Disease

Quarles¹,

Sherrard²,

Adler³

et al. 2003

Journal of the American Society of Nephrology

240

185

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Abstract. Current treatment of secondary hyperparathyroidism in chronic kidney failure with calcium and active vitamin D is potentially limited by hypercalcemia and hyperphosphatemia. AMG 073 represents a new class of compounds for the treatment of hyperparathyroidism known as calcimimetics, which reduce parathyroid hormone (PTH) synthesis and secretion by increasing the sensitivity of the parathyroid calcium-sensing receptor (CaR) to extracellular calcium. The current study evaluates the efficacy and safety of AMG 073 when added to conventional treatment of secondary hyperparathyroidism in end-stage renal disease (ESRD). Seventy-one hemodialysis patients with uncontrolled secondary hyperparathyroidism, despite standard therapy with calcium, phosphate binders, and active vitamin D sterols, were treated in this 18-wk, dosetitration study with single daily oral doses of AMG 073/ placebo up to 100 mg. Changes in plasma PTH, serum calcium, serum phosphorus, and calcium ϫ phosphorus levels were compared between AMG 073 and placebo groups. Mean PTH decreased by 33% in the AMG 073 patients compared with an increase of 3% in placebo patients (P ϭ 0.001). A significantly greater proportion of AMG 073 patients (44%) had a mean PTH Յ 250 pg/ml compared with placebo patients (20%; P ϭ 0.029). Also, a significantly greater proportion of AMG 073 patients (53%) had a decrease in PTH Ն30% compared with placebo patients (23%; P ϭ 0.009). Calcium ϫ phosphorus levels decreased by 7.9% in AMG 073 patients compared with an increase of 11.3% in placebo patients (P ϭ 0.013). Adverse event rates were low and mostly mild to moderate in severity; however, the incidence of vomiting was higher in AMG 073 patients. In this study, the calcimimetic AMG 073 at doses up to 100 mg for 18 wk provided a safe and effective means to attain significant reductions in PTH and calcium ϫ phosphorus levels in ESRD patients. AMG 073 represents a novel and promising therapy to improve the management of secondary hyperparathyroidism.The current standard treatment for secondary hyperparathyroidism in ESRD uses calcium supplementation, phosphate binders, and active vitamin D sterols in various combinations to attempt correction of hypocalcemia, hyperphosphatemia, and 1,25 (OH) 2 vitamin D 3 deficiency (1,2). Each component of this combined treatment strategy addresses abnormalities responsible for the pathogenesis of hyperparathyroidism, but each has limitations due to potential undesirable side effects at doses required to effectively suppress PTH hypersecretion (3-6). In this regard, treatment with vitamin D sterols is often complicated by hypercalcemia and hyperphosphatemia (7-10), resulting in elevate calcium ϫ phosphorus levels, predisposition to soft tissue calcification, and increased mortality risk in the ESRD population (11-15). Large doses of orally administered calcium to control hyperphosphatemia also predispose patients to episodes of hypercalcemia, chronic positive calcium balance, and increased soft tissue calcification in dialysis patients (15,...

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Dietary Phosphorus Restriction Reverses the Impaired Bone Mineralization in Vitamin D Receptor Knockout Mice

Cited by 30 publications

References 0 publications

Vitamin D endocrine system and the intestine

Vitamin D endocrine system and the intestine

Intestinal Na-P_icotransporter adaptation to dietary P_icontent in vitamin D receptor null mice

The Calcimimetic AMG 073 as a Potential Treatment for Secondary Hyperparathyroidism of End-Stage Renal Disease

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Dietary Phosphorus Restriction Reverses the Impaired Bone Mineralization in Vitamin D Receptor Knockout Mice

Cited by 30 publications

References 0 publications

Vitamin D endocrine system and the intestine

Vitamin D endocrine system and the intestine

Intestinal Na-Picotransporter adaptation to dietary Picontent in vitamin D receptor null mice

The Calcimimetic AMG 073 as a Potential Treatment for Secondary Hyperparathyroidism of End-Stage Renal Disease

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Intestinal Na-P_icotransporter adaptation to dietary P_icontent in vitamin D receptor null mice