BASIC RESEARCH

Parathyroid Hormone Regulates Fibroblast Growth Factor-23 in a Mouse Model of Primary Hyperparathyroidism

Takehisa Kawata, Yasuo Imanishi, Keisuke Kobayashi, Takami Miki, Andrew Arnold, Masaaki Inaba and Yoshiki Nishizawa
JASN October 2007, 18 (10) 2683-2688; DOI: https://doi.org/10.1681/ASN.2006070783

Abstract

The importance of fibroblast growth factor 23 (FGF-23) in the pathogenesis of phosphate wasting disorders has been established, but controversy remains about how parathyroid hormone (PTH), which also stimulates urinary phosphate excretion, regulates the circulating level of FGF-23. We found that the serum FGF-23 concentration was higher in PTH-cyclin D1 transgenic mice, a model of primary hyperparathyroidism, than in wild-type mice. The serum FGF-23 concentration was significantly and directly correlated with serum PTH and calcium, and inversely correlated with phosphate levels in 90- to 118-week-old mice (all P < 0.005). Quantitative real-time reverse-transcriptase PCR revealed abundant expression of fgf23 in bone, especially in calvaria. The fgf23 expression in calvaria was significantly higher in the transgenic mice compared to the wild-type mice, and correlated well with serum FGF-23 levels. There was a direct correlation between the expression of fgf23 and the expression of osteocalcin and ALP, suggesting that activation of osteoblasts is important in the regulation of FGF-23. Serum FGF-23 levels decreased in the transgenic mice after parathyroidectomy. In conclusion, PTH plays a major role in the regulation of serum FGF-23 level in primary hyperparathyroidism, likely via activation of osteoblasts in bone.

An excess of fibroblast growth factor-23 (FGF-23), a member of the FGF family, is now known to be a major factor in the development of hypophosphatemic rickets/osteomalacia, including X-linked hypophosphatemic rickets and oncogenic osteomalacia.1–3 Autosomal dominant hypophosphatemic rickets, a similar disorder characterized by renal phosphate wasting, has been reported to be associated with mutations of the FGF-23 gene4 that prevent its cleavage.5 Administration of recombinant FGF-23 decreases serum phosphate levels in mice by increasing renal phosphate excretion.6 Implantation of Chinese hamster ovary cells stably expressing FGF-23 into mice led to hypophosphatemic rickets in vivo,6 indicating the importance of FGF-23 in the development of hypophosphatemic rickets.

Plasma FGF-23 levels are directly and significantly correlated with serum parathyroid hormone (PTH), calcium, and phosphate levels in uremic patients who are on maintenance hemodialysis.7,8 There is some evidence that plasma FGF-23 levels may be regulated or affected by dietary phosphate. Recently, dietary consumption of phosphate was shown to regulate serum FGF-23 levels in both uremic rats9,10 and nonuremic mice.11 In addition, 1,25 dihydroxyvitamin D3 [1,25(OH)2D3] upregulates serum FGF-23 level in mice12,13 and in thyroparathyroidectomized rats without a corresponding increase in serum phosphate levels9, suggesting a role for both dietary phosphate and 1,25(OH)2D3 in FGF-23 secretion.

Elevated FGF-23 levels have also been reported in patients with primary hyperparathyroidism (PHPT). FGF-23 concentrations are significantly directly correlated with serum calcium and intact PTH levels and inversely correlated with creatinine clearance and phosphate concentration; of these, creatinine clearance and calcium are independently associated factors.14,15 Although both of these clinical studies suggested the importance of PTH action in the regulation of FGF-23 in patients with PHPT, serum FGF-23 levels decreased significantly after parathyroidectomy (PTX) in one study,15 whereas the decrease was NS in the other.14

Here we used PTH-cyclin D1 transgenic (PC2) mice, which exhibit parathyroid-targeted overexpression of the human cyclin D1 oncogene, as a model of PHPT. These mice develop not only abnormal parathyroid cell proliferation but also chronic biochemical hyperparathyroidism, with characteristic abnormalities in bone and, notably, a shift in the relationship between serum calcium and PTH.16,17 These mice eventually exhibited adenomatous-appearing parathyroid region with reduced calcium-sensing receptor expression.18

In this study, we attempted to determine the roles of PTH in the regulation of serum FGF-23 levels using PC2 mice. To investigate the sources of serum FGF-23 in mice, we analyzed fgf23 expression in various tissues by quantitative real-time reverse transcriptase–PCR (RT-PCR) and examined the correlation among fgf23 expression, other biochemical markers, and the circulating levels of the protein. We also performed PTX in PC2 mice to determine the influence of PTH oversecretion on elevated serum FGF-23 levels.

RESULTS

Serum FGF-23 in PC2 Mice

At 27 to 33 wk, the PC2 mice already showed significantly higher serum calcium levels than age-matched wild-type (WT) mice, and, at older ages, the mice exhibited typical signs of biochemical hyperparathyroidism, such as hypercalcemia, hypophosphatemia, and elevated PTH levels (Table 1). PC2 mice had significantly higher levels of serum FGF-23 than WT mice at all ages examined, and the levels increased significantly with age, reaching three times those of WT mice in 90- to 118-wk-old mice (Figure 1). Serum FGF-23 levels were significantly directly correlated with serum PTH and calcium levels and inversely correlated with serum phosphate levels in 90- to 118-wk-old mice (Figure 2). Serum 1,25(OH)2D levels were directly correlated with serum FGF-23 levels but not significantly. Serum urea nitrogen levels were not significantly different between PC2 mice and age-matched WT mice at any age (Table 1).

Figure 1.
Figure 1.

Changes in serum FGF-23 levels in WT and PC2 mice. PC2 mice had significantly higher levels of serum FGF-23 than WT mice at 27 to 33 wk of age. FGF-23 concentrations significantly increased with age in PC2 mice (P = 0.021 by two-way ANOVA), reaching three times the level of WT mice at 90 to 118 wk. Data are means ± SE. *P < 0.05 versus same-age WT mice; †versus PC2 mice at 27 to 33 wk; ¶versus PC2 mice at 60 to 75 wk by post hoc analysis (Games-Howell).

Figure 2.
Figure 2.

Correlation between serum FGF-23 concentration and other serum parameters in 90- to 118-wk-old mice. ○, WT mice (n = 6); •, PC2 mice (n = 18). Serum FGF-23 levels were correlated with serum PTH (A; r = 0.605, P = 0.004), calcium (B; r = 0.859, P < 0.001), and phosphate levels (C; r = −0.583, P = 0.002) by Pearson correlation analysis. Serum 1,25(OH)2D levels were directly correlated with serum FGF-23 levels but not significantly (D; r = 0.420, P = 0.083).

View this table:
Table 1.

Serum biochemistries of experimental micea

Tissue Expression of fgf23 and Osteoblastic Markers

For investigation of the sources of serum FGF-23 in mice, fgf23 expression was analyzed in various tissues from 90- to 118-wk-old PC2 and WT mice using quantitative real-time PCR. High fgf23 expression was observed in femur and calvaria and was 1.8 and 14.4 times higher than in the thymus of WT mice, respectively (Figure 3A). In PC2 mice, fgf23 expression was 15.2- and 54.6-fold in the femur and calvaria, respectively, compared with that in the thymus of WT mice (Figure 3A). When fgf23 expression was examined in more detail in bone, it was found to be 20.2-fold higher in calvaria and 2.7-fold in the femur of PC2 mice than in the same sites of WT mice (Figure 3B). The highest expression was observed in PC2 calvaria. The fgf23 expression levels in calvaria were significantly directly correlated with serum FGF-23 levels (Figure 4). fgf23 expression levels in calvaria were also significantly directly correlated with ALP and osteocalcin expression levels (Figure 5).

Figure 3.
Figure 3.

Tissue expression of fgf23 in 90- to 118-wk-old mice. (A) Quantitative real-time RT-PCR analyses of RNA from tissues of WT and PC2 mice were performed. □, WT mice; ▪, PC2 mice. Abundant expression was observed in femur and calvaria from both groups of mice. (B) fgf23 expression was further analyzed in calvaria, lumbar spine, and femur. Expression of fgf23 was significantly higher in PC2 calvaria than in WT calvaria (P = 0.0143, Mann-Whitney U test). Significant differences between PC2 and WT mice were also observed in the femur (P = 0.0272). Data are means ± SE of three to five WT and wight to 10 PC2 mice.

Figure 4.
Figure 4.

Correlation between serum FGF-23 levels and fgf23 expression levels in calvaria in 90- to 118-wk-old mice. ○, WT mice (n = 5); •, PC2 mice (n = 10). Serum FGF23 levels were significantly correlated with fgf23 expression levels in calvaria of PC2 mice (r = 0.811, P < 0.001) by Pearson correlation test.

Figure 5.
Figure 5.

Correlation between expression levels of fgf23 and osteoblastic markers in calvaria in 90- to 118-wk-old mice. ○, WT mice (n = 5); •, PC2 mice (n = 10). fgf23 expression levels were significantly correlated with the expression levels of both ALP (A; r = 0.705, P = 0.002) and osteocalcin (B; r = 0.789, P = 0.002) in calvaria of PC2 mice by Pearson correlation test.

Effect of PTX on Serum FGF-23 Levels

For investigation of the effect of PTH on serum FGF-23 levels, PTX was performed on 60- to 75-wk-old PC2 mice. The success of the PTX was confirmed by the presence of significant decreases in serum calcium and PTH levels and a significant increase in serum phosphate level 72 h after the PTX compared with pre-PTX levels (Table 2). By 72 h after PTX, serum FGF-23 levels had significantly decreased from 358 ± 35 to 196 ± 19 pg/ml (P < 0.001; Figure 6), reaching the levels of age-matched WT mice (193 ± 23 pg/ml; P = 0.938 versus PC2 mice 72 h after PTX).

Figure 6.
Figure 6.

PTX decreases serum FGF-23 levels in PC2 mice. PTX was performed on 60- to 75-wk-old PC2 mice. Blood samples were obtained before and 72 h after PTX. Values for each mouse are represented (•), along with the means ± SE of 10 mice (♦). ¶P = 0.0012 by paired t test.

View this table:
Table 2.

Changes in serum parameters after PTX in 60- to 75-wk-old PC2 micea

DISCUSSION

FGF-23 is a key regulator of serum phosphate and 1,25(OH)2D, but how it is regulated by PTH is still unclear. Our observations suggest that, in a mouse model of PHPT, the calvaria is a major source of circulating FGF-23, likely via osteoblast activation. Serum PTH and calcium levels highly correlated with serum FGF-23 levels, whereas serum phosphate seemed to have minor roles in FGF-23 regulation in PHPT mice with normal kidney function. The decrement in serum FGF-23 levels in PC2 mice after PTX suggests that PTH functions to stimulate FGF-23 secretion.

Serum FGF-23 concentrations in PC2 mice were initially elevated at 27 to 33 wk and gradually increased, followed by the development of PHPT. In 60- to 75-wk-old PC2 mice, mild PHPT was accompanied by significantly higher serum FGF-23 levels than in WT mice. After PTX, FGF-23 levels in PC2 mice significantly decreased to the levels of age-matched WT mice, indicating that PTH is a potential stimulator of serum FGF-23 levels in vivo in PHPT. In clinical studies of PHPT, circulating FGF-23 levels decreased significantly after PTX in patients with normal kidney function15 and decreased—but not significantly—in patients with renal insufficiency.14 Administration of vitamin D analogs9,19 and/or calcium,15 as well as renal insufficiency,20 may interfere with the decrement of circulating FGF-23 levels after PTX.

Expression of fgf23 was predominantly observed in bone, especially in calvaria,11,21,22 which also showed markedly increased expression in Hyp, a mouse homologue of X-linked hypophosphatemic rickets.21 In this study, PC2 mice had higher expression of fgf23 than WT mice in calvaria and femur, where cortical bone content is higher than in cancellous bone. This is in agreement with a previous report of FGF-23 expression in healthy human cortical bones.23 Expression of fgf23 in calvaria, which contains an extremely high amount of cortical bone, seemed to be a major determinant of serum FGF-23 levels in PC2 mice. The expression of fgf23 by cells at the sutures as well as osteoblasts22 may explain the high fgf23 expression in calvaria. We observed good correlation between fgf23 expression and the expression of osteoblastic markers, such as ALP and osteocalcin, suggesting that the activities of osteoblasts and/or osteocytes might be involved in the stimulation of FGF-23 by PTH.

We observed advanced PHPT in 90- to 118-wk-old PC2 mice, and serum parameters varied widely, as described previously.16 In these mice, serum FGF-23 levels were more strongly correlated with serum calcium levels than with PTH levels. The same trend was also reported in patients who had PHPT with14 and without15 renal insufficiency. Because PTH mobilizes calcium from the bone to the circulation, the direct correlation of FGF-23 with calcium would likely be a result of PTH activity. A stronger correlation with calcium than PTH was also observed in patients with PHPT14,15 and secondary hyperparathyroidism,7 but this does not negate the possibility of a direct effect of calcium on osteoblasts or osteocytes. Calcium has been reported to stimulate osteoblast proliferation directly through calcium-sensing receptor–mediated pathways,24,25 and the role of calcium-sensing receptor pathways on fgf23 expression in bone requires further study.

In previous studies, 1,25(OH)2D3 was found to upregulate serum FGF-23 levels in mice12,13 and in rats.9 Overexpression of a dominant negative vitamin D receptor inhibited 1,25(OH)2D3 stimulation of fgf23 promoter activity in vitro in osteoblasts,26 which suggested that 1,25(OH)2D3 is an important regulator of FGF-23 production in bone. Elevated serum 1,25(OH)2D levels induced by oversecretion of PTH were observed in patients with PHPT, and elevated 1,25(OH)2D levels may enhance FGF-23 production in bone. In this study, serum 1,25(OH)2D levels were directly correlated with serum FGF-23 levels but not significantly. In addition, a decrease in circulating FGF-23 was observed after PTX. In contrast, the decrease in the level of 1,25(OH)2D after PTX was not statistically significant. Similar results have been obtained in patients with PHPT.15 These observations suggest that 1,25(OH)2D is a positive regulator of serum FGF-23 levels but that its role is limited in PHPT.

FGF-23 has a phosphaturic effect, and its circulating levels may also be regulated or affected by serum phosphate levels. In uremic patients who are on maintenance hemodialysis, plasma FGF-23 levels are elevated and are correlated with inorganic phosphate, PTH, and corrected calcium.7,8 Serum FGF-23 levels are also correlated with serum phosphate levels in uremic rats.9 Recently, a direct correlation between serum FGF-23 and serum phosphate levels was observed in nonuremic mice consuming dramatically changed amounts of dietary phosphate.11 In contrast, no correlation between FGF-23 and serum phosphate levels was observed in nonuremic healthy humans,8,27 and a inverse correlation was seen in patients with PHPT.14,15 Even when alimentary intake of phosphorus is excessive, surplus phosphate is excreted very quickly by the kidneys, and hyperphosphatemia is not usually observed in healthy humans. In addition, hyperphosphaturia would be expected to occur in patients with PHPT secondary to elevated PTH levels. In this study, the inverse correlation between FGF-23 and phosphate levels was confirmed in vivo in a model of PHPT. Elevated FGF-23 levels in PHPT would presumably enhance the phosphaturia that is already accelerated by elevated PTH levels, resulting in hypophosphatemia.

Our observations suggest that FGF-23 secreted from bone, especially cortical bone such as calvaria, may contribute to elevated serum FGF-23 levels in hyperparathyroidism. PTH is a potential stimulator of the production of FGF-23. The combined reduction in serum phosphate by FGF-23 and PTH may prevent tissue damage, for example by preventing ectopic calcification by lowering the serum calcium-phosphate product in the presence of hypercalcemia caused by oversecretion of PTH in PHPT.

CONCISE METHODS

Experimental Animals

PC2 mice that overexpress the human cyclin D1 oncogene specifically in the parathyroid were used in this study as a model of PHPT.16 For selection of the mice bearing the transgene, offspring were genotyped by Southern blotting using h-cyclin D1 cDNA as a probe.16 PC2 and WT mice were used at three ages: 27 to 33, 60 to 75, and 90 to 118 wk. All mice were provided with a commercially available rodent diet, CE-2 (Crea Japan, Tokyo, Japan), containing 1.03% calcium and 0.97% phosphorus, and water ad libitum. The studies were approved by the appropriate institutional animal care committees at Osaka City University Graduate School of Medicine.

Measurement of Biochemical Parameters

Blood samples were collected from the orbital cavities of anesthetized mice in the morning (10:00 to 11:00 a.m.). Serum FGF-23 was measured with sandwich ELISA kits (Kainos Laboratories, Tokyo, Japan). Serum PTH was measured with rat PTH IRMA kits (Immutopics, San Clemente, CA). Serum 1,25(OH)2D concentrations were measured with RIA kits (Immunodiagnostic Systems Ltd, Boldon, England). Serum biochemistries, including total calcium, phosphate, urea nitrogen, and alkaline phosphatase, were determined with a series of TESTWAKO kits (Wako Chemical Co., Ltd., Tokyo, Japan).

PTX of PC2 Mice

PTX was performed on 60- to 75-wk-old male anesthetized PC2 mice. Because the parathyroid glands of PC2 mice are large enough to identify under a stereoscopic microscope, we were able to excise only the parathyroid glands without removing the thyroid glands.

Quantitative Real-Time RT-PCR

Total RNA was isolated from fresh-frozen surgically resected mouse tissues using the standard protocol of the RNA/DNA Kit (QIAGEN, Hilden, Germany). The total RNA was reverse-transcribed to cDNA using a TaqMan reverse transcription kit (Applied Biosystems, Foster City, CA). Amplification and detection were carried out in 96-well optical plates on an ABI Prism 7000 sequence detector (Applied Biosystems) with TaqMan Universal PCR 2× master mix, 20× Assay-on-Demand Gene Expression Assay Mix (Applied Biosystems), and sample cDNA in a final volume of 50 μl per reaction. The FGF23, ALP, osteocalcin, and 18S ribosomal gene sequences were amplified for quantitative PCR with an initial hold of 50°C for 2 min to activate the No AmpErase UNG and a hold of 95°C for 10 min to activate AmpliTaq Gold polymerase, followed by 40 cycles of 95°C for 15 s and 60°C for 1 min. The products were analyzed with the manufacturer's software, SDS 1.1 (Applied Biosystems).

Statistical Analyses

Differences between the mean values of the groups were evaluated by two-way ANOVA. Correlation coefficients between two parameters were obtained using Pearson correlation analyses. Differences in fgf23 expression were analyzed with the Mann-Whitney U test. Differences in serum parameters between preoperative and postoperative samples were evaluated by the paired t test. Results are expressed as means ± SE. All statistical analyses were performed by SPSS 14.0J (SPSS Japan, Tokyo, Japan).

DISCLOSURES

None.

Acknowledgments

This research was supported in part by grant OKF05-0010 from the Osaka Kidney Foundation (to Y.I.), Grants-in-Aid from the Renal Society for Metabolic Bone Diseases (to Y.N.), and a grant award from the Eleventh and Valedictory Workshop on Cell Biology of Bone and Cartilage in Health and Disease (to Y.I.).

We gratefully thank Prof. Nobuyuki Ito (Kyoto University Graduate School of Pharmaceutical Sciences) for providing us with the m-fgf23 cDNA and Dr. Mitsuru Fukui (Osaka City University Graduate School of Medicine) for assistance with statistical analyses.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

REFERENCES

  1. ↵
    Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, Yamamoto T, Hampson G, Koshiyama H, Ljunggren O, Oba K, Yang IM, Miyauchi A, Econs MJ, Lavigne J, Juppner H: Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med 348 : 1656 –1663, 2003
    OpenUrlCrossRefPubMed
  2. White KE, Jonsson KB, Carn G, Hampson G, Spector TD, Mannstadt M, Lorenz-Depiereux B, Miyauchi A, Yang IM, Ljunggren O, Meitinger T, Strom TM, Juppner H, Econs MJ: The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting. J Clin Endocrinol Metab 86 : 497 –500, 2001
    OpenUrlCrossRefPubMed
  3. ↵
    Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T, Takeuchi Y, Fujita T, Nakahara K, Yamashita T, Fukumoto S: Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab 87 : 4957 –4960, 2002
    OpenUrlCrossRefPubMed
  4. ↵
    The ADHR Consortium: Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26 : 345 –348, 2000
    OpenUrlCrossRefPubMed
  5. ↵
    White KE, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ: Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int 60 : 2079 –2086, 2001
    OpenUrlCrossRefPubMed
  6. ↵
    Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T: Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A 98 : 6500 –6505, 2001
    OpenUrlAbstract/FREE Full Text
  7. ↵
    Imanishi Y, Inaba M, Nakatsuka K, Nagasue K, Okuno S, Yoshihara A, Miura M, Miyauchi A, Kobayashi K, Miki T, Shoji T, Ishimura E, Nishizawa Y: FGF-23 in patients with end-stage renal disease on hemodialysis. Kidney Int 65 : 1943 –1946, 2004
    OpenUrlCrossRefPubMed
  8. ↵
    Larsson T, Nisbeth U, Ljunggren O, Juppner H, Jonsson KB: Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int 64 : 2272 –2279, 2003
    OpenUrlCrossRefPubMed
  9. ↵
    Saito H, Maeda A, Ohtomo S, Hirata M, Kusano K, Kato S, Ogata E, Segawa H, Miyamoto K, Fukushima N: Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem 280 : 2543 –2549, 2005
    OpenUrlAbstract/FREE Full Text
  10. ↵
    Nagano N, Miyata S, Abe M, Kobayashi N, Wakita S, Yamashita T, Wada M: Effect of manipulating serum phosphorus with phosphate binder on circulating PTH and FGF23 in renal failure rats. Kidney Int 69 : 531 –537, 2006
    OpenUrlCrossRefPubMed
  11. ↵
    Perwad F, Azam N, Zhang MY, Yamashita T, Tenenhouse HS, Portale AA: Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology 146 : 5358 –5364, 2005
    OpenUrlCrossRefPubMed
  12. ↵
    Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T: FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19 : 429 –435, 2004
    OpenUrlCrossRefPubMed
  13. ↵
    Kolek OI, Hines ER, Jones MD, LeSueur LK, Lipko MA, Kiela PR, Collins JF, Haussler MR, Ghishan FK: 1alpha,25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol 289 : G1036 –G1042, 2005
    OpenUrlCrossRefPubMed
  14. ↵
    Yamashita H, Yamashita T, Miyamoto M, Shigematsu T, Kazama JJ, Shimada T, Yamazaki Y, Fukumoto S, Fukagaw M, Noguchi S: Fibroblast growth factor (FGF)-23 in patients with primary hyperparathyroidism. Eur J Endocrinol 151 : 55 –60, 2004
    OpenUrlAbstract
  15. ↵
    Kobayashi K, Imanishi Y, Miyauchi A, Onoda N, Kawata T, Tahara H, Goto H, Miki T, Ishimura E, Sugimoto T, Ishikawa T, Inaba M, Nishizawa Y: Regulation of plasma fibroblast growth factor 23 by calcium in primary hyperparathyroidism. Eur J Endocrinol 154 : 93 –99, 2006
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Imanishi Y, Hosokawa Y, Yoshimoto K, Schipani E, Mallya S, Papanikolaou A, Kifor O, Tokura T, Sablosky M, Ledgard F, Gronowicz G, Wang TC, Schmidt EV, Hall C, Brown EM, Bronson R, Arnold A: Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice. J Clin Invest 107 : 1093 –1102, 2001
    OpenUrlCrossRefPubMed
  17. ↵
    Mallya SM, Gallagher JJ, Wild YK, Kifor O, Costa-Guda J, Saucier K, Brown EM, Arnold A: Abnormal parathyroid cell proliferation precedes biochemical abnormalities in a mouse model of primary hyperparathyroidism. Mol Endocrinol 19 : 2603 –2609, 2005
    OpenUrlCrossRefPubMed
  18. ↵
    Kawata T, Imanishi Y, Kobayashi K, Kenko T, Wada M, Ishimura E, Miki T, Nagano N, Inaba M, Arnold A, Nishizawa Y: Relationship between parathyroid calcium-sensing receptor expression and potency of the calcimimetic, cinacalcet, in suppressing parathyroid hormone secretion in an in vivo murine model of primary hyperparathyroidism. Eur J Endocrinol 153 : 587 –594, 2005
    OpenUrl
  19. ↵
    Yu X, Sabbagh Y, Davis SI, Demay MB, White KE: Genetic dissection of phosphate- and vitamin D-mediated regulation of circulating Fgf23 concentrations. Bone 36 : 971 –977, 2005
    OpenUrlCrossRefPubMed
  20. ↵
    Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G, Juppner H, Wolf M: Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 16 : 2205 –2215, 2005
    OpenUrlAbstract/FREE Full Text
  21. ↵
    Liu S, Guo R, Simpson LG, Xiao ZS, Burnham CE, Quarles LD: Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem 278 : 37419 –37426, 2003
    OpenUrlAbstract/FREE Full Text
  22. ↵
    Sitara D, Razzaque MS, Hesse M, Yoganathan S, Taguchi T, Erben RG, Juppner H, Lanske B: Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 23 : 421 –432, 2004
    OpenUrlCrossRefPubMed
  23. ↵
    Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, Waguespack S, Gupta A, Hannon T, Econs MJ, Bianco P, Gehron Robey P: FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest 112 : 683 –692, 2003
    OpenUrlCrossRefPubMed
  24. ↵
    Mailland M, Waelchli R, Ruat M, Boddeke HG, Seuwen K: Stimulation of cell proliferation by calcium and a calcimimetic compound. Endocrinology 138 : 3601 –3605, 1997
    OpenUrlCrossRefPubMed
  25. ↵
    Dvorak MM, Siddiqua A, Ward DT, Carter DH, Dallas SL, Nemeth EF, Riccardi D: Physiological changes in extracellular calcium concentration directly control osteoblast function in the absence of calciotropic hormones. Proc Natl Acad Sci U S A 101 : 5140 –5145, 2004
    OpenUrlAbstract/FREE Full Text
  26. ↵
    Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, Quarles LD: Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 17 : 1305 –1315, 2006
    OpenUrlAbstract/FREE Full Text
  27. ↵
    Ferrari SL, Bonjour JP, Rizzoli R: Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab 90 : 1519 –1524, 2005
    OpenUrlCrossRefPubMed
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Parathyroid Hormone Regulates Fibroblast Growth Factor-23 in a Mouse Model of Primary Hyperparathyroidism
Takehisa Kawata, Yasuo Imanishi, Keisuke Kobayashi, Takami Miki, Andrew Arnold, Masaaki Inaba, Yoshiki Nishizawa
JASN Oct 2007, 18 (10) 2683-2688; DOI: 10.1681/ASN.2006070783
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