Fibroblast growth factor-23 regulates parathyroid hormone and 1α-hydroxylase expression in cultured bovine parathyroid cells

Krajisnik, Tijana; Björklund, Peyman; Marsell, Richard; Ljunggren, Östen; Åkerström, Göran; Jonsson, Kenneth B.; Westin, Gunnar; Larsson, Tobias E.

doi:10.1677/joe-07-0267

Cited by 425 publications

(289 citation statements)

References 40 publications

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“…Furthermore, it is of interest that this patient's hyperparathyroidism occurs in the presence of hypophosphatemia and not the elevated phosphate levels that accompany renal failure. Moreover, ␣-Klotho has been reported to mediate PTH secretion in vitro through its maintenance of cell surface Na ϩ /K ϩ -ATPase activity (22); conversely, FGF23 has recently been shown to inhibit expression of PTH mRNA and secretion of PTH from parathyroid cells (35). Whether the elevated FGF23 level seen in our patient is the direct result of increased ␣-Klotho (for example, if degradation of FGF23 were prevented by interaction with ␣-Klotho) or is part of a negativefeedback loop responding to hyperparathyroidism is difficult to discern at present.…”

Section: Discussionmentioning

confidence: 99%

A translocation causing increased α-Klotho level results in hypophosphatemic rickets and hyperparathyroidism

Brownstein

Adler²,

Nelson‐Williams³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

218

149

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Phosphate homeostasis is central to diverse physiologic processes including energy homeostasis, formation of lipid bilayers, and bone formation. Reduced phosphate levels due to excessive renal loss cause hypophosphatemic rickets, a disease characterized by prominent bone defects; conversely, hyperphosphatemia, a major complication of renal failure, is accompanied by parathyroid hyperplasia, hyperparathyroidism, and osteodystrophy. Here, we define a syndrome featuring both hypophosphatemic rickets and hyperparathyroidism due to parathyroid hyperplasia as well as other skeletal abnormalities. We show that this disease is due to a de novo translocation with a breakpoint adjacent to ␣-Klotho, which encodes a ␤-glucuronidase, and is implicated in aging and regulation of FGF signaling. Plasma ␣-Klotho levels and ␤-glucuronidase activity are markedly increased in the affected patient; unexpectedly, the circulating FGF23 level is also markedly elevated. These findings suggest that the elevated ␣-Klotho level mimics aspects of the normal response to hyperphosphatemia and implicate ␣-Klotho in the selective regulation of phosphate levels and in the regulation of parathyroid mass and function; they also have implications for the pathogenesis and treatment of renal osteodystrophy in patients with kidney failure.bone ͉ endocrinology ͉ genetics ͉ phosphorus T he maintenance of normal phosphate homeostasis is critical for diverse biochemical processes in vivo. Its importance is illustrated by disorders featuring hypophosphatemia due to excessive renal phosphate loss. Affected patients develop rickets, a disorder in which abnormal mineralization of bone and growth plate cartilage results in diminished bone strength, deformity, short stature, and bone pain. Rapidly growing bones of the lower extremities generally show the most striking abnormalities (1). Conversely, high phosphate levels may also have adverse physiologic effects. These are most pronounced in patients with chronic kidney disease (CKD) who develop hyperphosphatemia due to impaired renal clearance. These patients develop hyperparathyroidism and renal osteodystrophy.The kidney plays a predominant role in the regulation of serum phosphorus levels. The vast majority of phosphate reabsorption occurs in the proximal tubule and is mediated by the sodium-phosphate cotransporter type IIa (NaPi-IIa), with additional contributions from the related protein NaPi-IIc (2, 3). Parathyroid hormone (PTH) has been considered the major regulator of NaPi-IIa and NaPi-IIc density in the proximal tubular cell apical membrane (3, 4), promoting the rapid removal of NaPi-IIa from the membrane and its subsequent degradation (5). In addition, high phosphate levels are known to promote proliferation of parathyroid cells and enhance PTH secretion and mRNA stability; these effects have been speculated to be mediated by means of reduced serum Ca 2ϩ levels, but the mechanism is uncertain (6-9).More recently, FGF23 and its receptor have been recognized to play fundamental roles in phosphate homeos...

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Section: Discussionmentioning

confidence: 99%

A translocation causing increased α-Klotho level results in hypophosphatemic rickets and hyperparathyroidism

Brownstein

Adler²,

Nelson‐Williams³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

218

149

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“…The reduction in PTH found in Ksp-KL 2/2 mice could could either be caused by higher systemic calcium levels or the fact that FGF23 inhibits PTH synthesis and secretion by directly targeting the parathyroid glands. 23,24 In contrast, Ksp-KL 2/2 mice challenged with a high-phosphate diet had higher PTH than wild-type littermates. The underlying mechanisms remain unclear.…”

Section: /2mentioning

confidence: 94%

Targeted Deletion of Klotho in Kidney Distal Tubule Disrupts Mineral Metabolism

Olauson

Lindberg

Amin

et al. 2012

Journal of the American Society of Nephrology

132

110

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Renal Klotho controls mineral metabolism by directly modulating tubular reabsorption of phosphate and calcium and by acting as a co-receptor for the phosphaturic and vitamin D-regulating hormone fibroblast growth factor-23 (FGF23). Klotho null mice have a markedly abnormal phenotype. We sought to determine effects of renal-specific and partial deletion of Klotho to facilitate investigation of its roles in health and disease. We generated a mouse model with partial deletion of Klotho in distal tubular segments (Ksp-KL 2/2 ).In contrast to Klotho null mice, Ksp-KL 2/2 mice were fertile, had a normal gross phenotype, and did not have vascular or tubular calcification on renal histology. However, Ksp-KL 2/2 mice were hyperphosphatemic with elevated FGF23 levels and abundant expression of the sodium-phosphate cotransporter Npt2a at the brush border membrane. Serum calcium and 1,25-dihydroxyvitamin D 3 levels were normal but parathyroid hormone levels were decreased. TRPV5 protein was reduced with a parallel mild increase in urinary calcium excretion. Renal expression of vitamin D regulatory enzymes and vitamin D receptor was higher in Ksp-KL 2/2 mice than controls, suggesting increased turnover of vitamin D metabolites and a functional increase in vitamin D signaling. There was a threshold effect of residual renal Klotho expression on FGF23: deletion of .70% of Klotho resulted in FGF23 levels 30-250 times higher than in wild-type mice. A subgroup of Ksp-KL 2/2 mice with normal phosphate levels had elevated FGF23, suggesting a Klothoderived renal-bone feedback loop. Taken together, renal FGF23-Klotho signaling, which is disrupted in CKD, is essential for homeostatic control of mineral metabolism.

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“…[1][2][3][4] Parathyroid cells also possess FGFR-klotho receptors, and experimental studies have shown that FGF23 inhibits parathyroid hormone (PTH) production and secretion. [5][6][7] However, in uremic animals, hyperplastic parathyroid glands fail to respond to FGF23 because the expression of FGFR-klotho is downregulated. [7][8][9][10][11] FGF23 effectively increases the output and decreases the input of phosphorus because it directly increases phosphaturia and indirectly decreases intestinal phosphorus absorption by decreasing calcitriol values.…”

mentioning

confidence: 99%

Calcium Deficiency Reduces Circulating Levels of FGF23

Rodríguez‐Ortiz

López²,

Muñoz‐Castañeda³

et al. 2012

Journal of the American Society of Nephrology

189

105

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Fibroblast growth factor (FGF) 23 inhibits calcitriol production, which could exacerbate calcium deficiency or hypocalcemia unless calcium itself modulates FGF23 in this setting. In Wistar rats with normal renal function fed a diet low in both calcium and vitamin D, the resulting hypocalcemia was associated with low FGF23 despite high parathyroid hormone (PTH) and high calcitriol levels. FGF23 correlated positively with calcium and negatively with PTH. Addition of high dietary phosphorus to this diet increased FGF23 except in rats with hypocalcemia despite high PTH levels. In parathyroidectomized rats, an increase in dietary calcium for 10 days increased serum calcium, with an associated increase in FGF23, decrease in calcitriol, and no change in phosphorus. Also in parathyroidectomized rats, FGF23 increased significantly 6 hours after administration of calcium gluconate. Taken together, these results suggest that hypocalcemia reduces the circulating concentrations of FGF23. This decrease in FGF23 could be a response to avoid a subsequent reduction in calcitriol, which could exacerbate hypocalcemia. 23: 119023: -119723: , 201223: . doi: 10.1681 Fibroblast growth factor (FGF) 23 production is stimulated by both calcitriol and phosphorus intake. FGF23 acts through FGFR-klotho receptors in the kidney to induce phosphaturia, a decrease in 1-a-hydroxylase activity, and an increase in 24-hydroxylase activity. The latter two effects decrease the synthesis and increase the degradation of calcitriol, respectively. 1-4 Parathyroid cells also possess FGFR-klotho receptors, and experimental studies have shown that FGF23 inhibits parathyroid hormone (PTH) production and secretion. [5][6][7] However, in uremic animals, hyperplastic parathyroid glands fail to respond to FGF23 because the expression of FGFR-klotho is downregulated. [7][8][9][10][11] FGF23 effectively increases the output and decreases the input of phosphorus because it directly increases phosphaturia and indirectly decreases intestinal phosphorus absorption by decreasing calcitriol values. However, a conflict will arise if high FGF23 inhibits calcitriol production in a setting of calcium deficiency/hypocalcemia, where high calcitriol is needed to increase intestinal calcium absorption. We have previously observed in parathyroidectomized (PTX) rats with decreased serum J Am Soc Nephrol

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Fibroblast growth factor-23 regulates parathyroid hormone and 1α-hydroxylase expression in cultured bovine parathyroid cells

Cited by 425 publications

References 40 publications

A translocation causing increased α-Klotho level results in hypophosphatemic rickets and hyperparathyroidism

A translocation causing increased α-Klotho level results in hypophosphatemic rickets and hyperparathyroidism

Targeted Deletion of Klotho in Kidney Distal Tubule Disrupts Mineral Metabolism

Calcium Deficiency Reduces Circulating Levels of FGF23

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