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*
Departments of * Metabolism, Endocrinology and Molecular Medicine and Geriatrics and Neurology, Osaka City University Graduate School of Medicine, Osaka, Japan; and Center for Molecular Medicine, University of Connecticut School of Medicine, Farmington, Connecticut
Correspondence: Dr. Yasuo Imanishi, Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. Phone: +81-6-6645-3806; Fax: +81-6-6645-3808; E-mail: imanishi{at}med.osaka-cu.ac.jp
Received for publication July 26, 2006.
Accepted for publication May 31, 2007.
The importance of fibroblast growth factor 23 (FGF-23) in thepathogenesis of phosphate wasting disorders has been established,but controversy remains about how parathyroid hormone (PTH),which also stimulates urinary phosphate excretion, regulatesthe circulating level of FGF-23. We found that the serum FGF-23concentration was higher in PTH-cyclin D1 transgenic mice, amodel of primary hyperparathyroidism, than in wild-type mice.The serum FGF-23 concentration was significantly and directlycorrelated with serum PTH and calcium, and inversely correlatedwith phosphate levels in 90- to 118-week-old mice (all P <0.005). Quantitative real-time reverse-transcriptase PCR revealedabundant expression of fgf23 in bone, especially in calvaria.The fgf23 expression in calvaria was significantly higher inthe transgenic mice compared to the wild-type mice, and correlatedwell with serum FGF-23 levels. There was a direct correlationbetween the expression of fgf23 and the expression of osteocalcinand ALP, suggesting that activation of osteoblasts is importantin the regulation of FGF-23. Serum FGF-23 levels decreased inthe transgenic mice after parathyroidectomy. In conclusion,PTH plays a major role in the regulation of serum FGF-23 levelin primary hyperparathyroidism, likely via activation of osteoblastsin bone.
An excess of fibroblast growth factor-23 (FGF-23), a memberof the FGF family, is now known to be a major factor in thedevelopment of hypophosphatemic rickets/osteomalacia, includingX-linked hypophosphatemic rickets and oncogenic osteomalacia.1–3Autosomal dominant hypophosphatemic rickets, a similar disordercharacterized by renal phosphate wasting, has been reportedto be associated with mutations of the FGF-23 gene4 that preventits cleavage.5 Administration of recombinant FGF-23 decreasesserum phosphate levels in mice by increasing renal phosphateexcretion.6 Implantation of Chinese hamster ovary cells stablyexpressing FGF-23 into mice led to hypophosphatemic ricketsin vivo,6 indicating the importance of FGF-23 in the developmentof hypophosphatemic rickets.
Plasma FGF-23 levels are directly and significantly correlatedwith serum parathyroid hormone (PTH), calcium, and phosphatelevels in uremic patients who are on maintenance hemodialysis.7,8There is some evidence that plasma FGF-23 levels may be regulatedor affected by dietary phosphate. Recently, dietary consumptionof phosphate was shown to regulate serum FGF-23 levels in bothuremic rats9,10 and nonuremic mice.11 In addition, 1,25 dihydroxyvitaminD3 [1,25(OH)2D3] upregulates serum FGF-23 level in mice12,13and in thyroparathyroidectomized rats without a correspondingincrease in serum phosphate levels9, suggesting a role for bothdietary phosphate and 1,25(OH)2D3 in FGF-23 secretion.
Elevated FGF-23 levels have also been reported in patients withprimary hyperparathyroidism (PHPT). FGF-23 concentrations aresignificantly directly correlated with serum calcium and intactPTH levels and inversely correlated with creatinine clearanceand phosphate concentration; of these, creatinine clearanceand calcium are independently associated factors.14,15 Althoughboth of these clinical studies suggested the importance of PTHaction in the regulation of FGF-23 in patients with PHPT, serumFGF-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 exhibitparathyroid-targeted overexpression of the human cyclin D1 oncogene,as a model of PHPT. These mice develop not only abnormal parathyroidcell proliferation but also chronic biochemical hyperparathyroidism,with characteristic abnormalities in bone and, notably, a shiftin the relationship between serum calcium and PTH.16,17 Thesemice eventually exhibited adenomatous-appearing parathyroidregion with reduced calcium-sensing receptor expression.18
In this study, we attempted to determine the roles of PTH inthe regulation of serum FGF-23 levels using PC2 mice. To investigatethe sources of serum FGF-23 in mice, we analyzed fgf23 expressionin 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 theprotein. We also performed PTX in PC2 mice to determine theinfluence of PTH oversecretion on elevated serum FGF-23 levels.
Serum FGF-23 in PC2 Mice
At 27 to 33 wk, the PC2 mice already showed significantly higherserum calcium levels than age-matched wild-type (WT) mice, and,at older ages, the mice exhibited typical signs of biochemicalhyperparathyroidism, such as hypercalcemia, hypophosphatemia,and elevated PTH levels (Table 1). PC2 mice had significantlyhigher levels of serum FGF-23 than WT mice at all ages examined,and the levels increased significantly with age, reaching threetimes those of WT mice in 90- to 118-wk-old mice (Figure 1).Serum FGF-23 levels were significantly directly correlated withserum PTH and calcium levels and inversely correlated with serumphosphate levels in 90- to 118-wk-old mice (Figure 2). Serum1,25(OH)2D levels were directly correlated with serum FGF-23levels but not significantly. Serum urea nitrogen levels werenot significantly different between PC2 mice and age-matchedWT mice at any age (Table 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. 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).
Tissue Expression of fgf23 and Osteoblastic Markers
For investigation of the sources of serum FGF-23 in mice, fgf23expression was analyzed in various tissues from 90- to 118-wk-oldPC2 and WT mice using quantitative real-time PCR. High fgf23expression was observed in femur and calvaria and was 1.8 and14.4 times higher than in the thymus of WT mice, respectively(Figure 3A). In PC2 mice, fgf23 expression was 15.2- and 54.6-foldin the femur and calvaria, respectively, compared with thatin the thymus of WT mice (Figure 3A). When fgf23 expressionwas examined in more detail in bone, it was found to be 20.2-foldhigher in calvaria and 2.7-fold in the femur of PC2 mice thanin the same sites of WT mice (Figure 3B). The highest expressionwas observed in PC2 calvaria. The fgf23 expression levels incalvaria were significantly directly correlated with serum FGF-23levels (Figure 4). fgf23 expression levels in calvaria werealso significantly directly correlated with ALP and osteocalcinexpression levels (Figure 5).
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. 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. 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 successof the PTX was confirmed by the presence of significant decreasesin serum calcium and PTH levels and a significant increase inserum phosphate level 72 h after the PTX compared with pre-PTXlevels (Table 2). By 72 h after PTX, serum FGF-23 levels hadsignificantly decreased from 358 ± 35 to 196 ±19 pg/ml (P < 0.001; Figure 6), reaching the levels of age-matchedWT mice (193 ± 23 pg/ml; P = 0.938 versus PC2 mice 72h after PTX).
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.
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 observationssuggest that, in a mouse model of PHPT, the calvaria is a majorsource of circulating FGF-23, likely via osteoblast activation.Serum PTH and calcium levels highly correlated with serum FGF-23levels, whereas serum phosphate seemed to have minor roles inFGF-23 regulation in PHPT mice with normal kidney function.The decrement in serum FGF-23 levels in PC2 mice after PTX suggeststhat PTH functions to stimulate FGF-23 secretion.
Serum FGF-23 concentrations in PC2 mice were initially elevatedat 27 to 33 wk and gradually increased, followed by the developmentof PHPT. In 60- to 75-wk-old PC2 mice, mild PHPT was accompaniedby significantly higher serum FGF-23 levels than in WT mice.After PTX, FGF-23 levels in PC2 mice significantly decreasedto the levels of age-matched WT mice, indicating that PTH isa potential stimulator of serum FGF-23 levels in vivo in PHPT.In clinical studies of PHPT, circulating FGF-23 levels decreasedsignificantly after PTX in patients with normal kidney function15and decreased—but not significantly—in patientswith renal insufficiency.14 Administration of vitamin D analogs9,19and/or calcium,15 as well as renal insufficiency,20 may interferewith the decrement of circulating FGF-23 levels after PTX.
Expression of fgf23 was predominantly observed in bone, especiallyin calvaria,11,21,22 which also showed markedly increased expressionin Hyp, a mouse homologue of X-linked hypophosphatemic rickets.21In this study, PC2 mice had higher expression of fgf23 thanWT mice in calvaria and femur, where cortical bone content ishigher than in cancellous bone. This is in agreement with aprevious report of FGF-23 expression in healthy human corticalbones.23 Expression of fgf23 in calvaria, which contains anextremely high amount of cortical bone, seemed to be a majordeterminant of serum FGF-23 levels in PC2 mice. The expressionof fgf23 by cells at the sutures as well as osteoblasts22 mayexplain the high fgf23 expression in calvaria. We observed goodcorrelation between fgf23 expression and the expression of osteoblasticmarkers, such as ALP and osteocalcin, suggesting that the activitiesof osteoblasts and/or osteocytes might be involved in the stimulationof FGF-23 by PTH.
We observed advanced PHPT in 90- to 118-wk-old PC2 mice, andserum parameters varied widely, as described previously.16 Inthese mice, serum FGF-23 levels were more strongly correlatedwith serum calcium levels than with PTH levels. The same trendwas also reported in patients who had PHPT with14 and without15renal insufficiency. Because PTH mobilizes calcium from thebone to the circulation, the direct correlation of FGF-23 withcalcium would likely be a result of PTH activity. A strongercorrelation with calcium than PTH was also observed in patientswith PHPT14,15 and secondary hyperparathyroidism,7 but thisdoes not negate the possibility of a direct effect of calciumon osteoblasts or osteocytes. Calcium has been reported to stimulateosteoblast proliferation directly through calcium-sensing receptor–mediatedpathways,24,25 and the role of calcium-sensing receptor pathwayson fgf23 expression in bone requires further study.
In previous studies, 1,25(OH)2D3 was found to upregulate serumFGF-23 levels in mice12,13 and in rats.9 Overexpression of adominant negative vitamin D receptor inhibited 1,25(OH)2D3 stimulationof fgf23 promoter activity in vitro in osteoblasts,26 whichsuggested that 1,25(OH)2D3 is an important regulator of FGF-23production in bone. Elevated serum 1,25(OH)2D levels inducedby oversecretion of PTH were observed in patients with PHPT,and elevated 1,25(OH)2D levels may enhance FGF-23 productionin bone. In this study, serum 1,25(OH)2D levels were directlycorrelated with serum FGF-23 levels but not significantly. Inaddition, a decrease in circulating FGF-23 was observed afterPTX. In contrast, the decrease in the level of 1,25(OH)2D afterPTX was not statistically significant. Similar results havebeen obtained in patients with PHPT.15 These observations suggestthat 1,25(OH)2D is a positive regulator of serum FGF-23 levelsbut that its role is limited in PHPT.
FGF-23 has a phosphaturic effect, and its circulating levelsmay also be regulated or affected by serum phosphate levels.In uremic patients who are on maintenance hemodialysis, plasmaFGF-23 levels are elevated and are correlated with inorganicphosphate, PTH, and corrected calcium.7,8 Serum FGF-23 levelsare also correlated with serum phosphate levels in uremic rats.9Recently, a direct correlation between serum FGF-23 and serumphosphate levels was observed in nonuremic mice consuming dramaticallychanged amounts of dietary phosphate.11 In contrast, no correlationbetween FGF-23 and serum phosphate levels was observed in nonuremichealthy humans,8,27 and a inverse correlation was seen in patientswith PHPT.14,15 Even when alimentary intake of phosphorus isexcessive, surplus phosphate is excreted very quickly by thekidneys, and hyperphosphatemia is not usually observed in healthyhumans. In addition, hyperphosphaturia would be expected tooccur in patients with PHPT secondary to elevated PTH levels.In this study, the inverse correlation between FGF-23 and phosphatelevels was confirmed in vivo in a model of PHPT. Elevated FGF-23levels in PHPT would presumably enhance the phosphaturia thatis already accelerated by elevated PTH levels, resulting inhypophosphatemia.
Our observations suggest that FGF-23 secreted from bone, especiallycortical bone such as calvaria, may contribute to elevated serumFGF-23 levels in hyperparathyroidism. PTH is a potential stimulatorof the production of FGF-23. The combined reduction in serumphosphate by FGF-23 and PTH may prevent tissue damage, for exampleby preventing ectopic calcification by lowering the serum calcium-phosphateproduct in the presence of hypercalcemia caused by oversecretionof PTH in PHPT.
Experimental Animals
PC2 mice that overexpress the human cyclin D1 oncogene specificallyin the parathyroid were used in this study as a model of PHPT.16For selection of the mice bearing the transgene, offspring weregenotyped by Southern blotting using h-cyclin D1 cDNA as a probe.16PC2 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 commerciallyavailable rodent diet, CE-2 (Crea Japan, Tokyo, Japan), containing1.03% calcium and 0.97% phosphorus, and water ad libitum. Thestudies were approved by the appropriate institutional animalcare committees at Osaka City University Graduate School ofMedicine.
Measurement of Biochemical Parameters
Blood samples were collected from the orbital cavities of anesthetizedmice in the morning (10:00 to 11:00 a.m.). Serum FGF-23 wasmeasured 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 measuredwith RIA kits (Immunodiagnostic Systems Ltd, Boldon, England).Serum biochemistries, including total calcium, phosphate, ureanitrogen, and alkaline phosphatase, were determined with a seriesof TESTWAKO kits (Wako Chemical Co., Ltd., Tokyo, Japan).
PTX of PC2 Mice
PTX was performed on 60- to 75-wk-old male anesthetized PC2mice. Because the parathyroid glands of PC2 mice are large enoughto identify under a stereoscopic microscope, we were able toexcise only the parathyroid glands without removing the thyroidglands.
Quantitative Real-Time RT-PCR
Total RNA was isolated from fresh-frozen surgically resectedmouse tissues using the standard protocol of the RNA/DNA Kit(QIAGEN, Hilden, Germany). The total RNA was reverse-transcribedto cDNA using a TaqMan reverse transcription kit (Applied Biosystems,Foster City, CA). Amplification and detection were carried outin 96-well optical plates on an ABI Prism 7000 sequence detector(Applied Biosystems) with TaqMan Universal PCR 2x master mix,20x 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 sequenceswere amplified for quantitative PCR with an initial hold of50°C for 2 min to activate the No AmpErase UNG and a holdof 95°C for 10 min to activate AmpliTaq Gold polymerase,followed by 40 cycles of 95°C for 15 s and 60°C for1 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 evaluatedby two-way ANOVA. Correlation coefficients between two parameterswere obtained using Pearson correlation analyses. Differencesin fgf23 expression were analyzed with the Mann-Whitney U test.Differences in serum parameters between preoperative and postoperativesamples were evaluated by the paired t test. Results are expressedas means ± SE. All statistical analyses were performedby SPSS 14.0J (SPSS Japan, Tokyo, Japan).
This research was supported in part by grant OKF05-0010 fromthe Osaka Kidney Foundation (to Y.I.), Grants-in-Aid from theRenal Society for Metabolic Bone Diseases (to Y.N.), and a grantaward from the Eleventh and Valedictory Workshop on Cell Biologyof Bone and Cartilage in Health and Disease (to Y.I.).
We gratefully thank Prof. Nobuyuki Ito (Kyoto University GraduateSchool of Pharmaceutical Sciences) for providing us with them-fgf23 cDNA and Dr. Mitsuru Fukui (Osaka City University GraduateSchool of Medicine) for assistance with statistical analyses.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Abstract
Introduction
, 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).
, 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.
). ¶P = 0.0012 by paired t test.