Slide 1

Dr Imanishi: First of all, thank you very much for inviting me to present our paper in this symposium.

Slide 2

Mr. Chairman, ladies and gentleman. Oncogenic osteomalacia is a rare sporadic disease with hypophosphatemia. This is a case of adult-onset hypophosphatemic osteomalacia, who is unable to walk because of severe bone pains. Bone biopsy revealed increase in osteoid width and absence of tetracycline labeling, suggesting marked mineralization defect. By the resection of a tumor in his right instep, serum phosphate level and tubular maximum transport of phosphate (TmP/GFR) were normalized. The tumor was giant cell tumor with positive FGF-23 staining.

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In ADHR, the mutations in exon 2 of FGF-23 gene protect FGF-23 peptide from proteolysis, thereby potentially elevating FGF-23 level and leading to phosphate wasting in the patients.

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Causative tumor of oncogenic osteomalacia or OOM overexpress FGF-23 and its circulating levels are elevated in OOM and X-linked hypophosphatemic rickets or XLH patients, indicating that this growth factor has pathological roles in hypophosphatemic rickets or osteomalacia.

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In hypophosphatemic rickets or osteomalacia, the patients revealed low serum 1,25 dihydroxy vitamin D level and low tubular maximum transport of phosphate or TmP/GFR followed by hypophosphatemia. Circulating FGF-23 was elevated, but usually PTH and calcium levels were normal.

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Administration of recombinant FGF-23 or FGF-23 expressing vector reduced Tmp/GFR in vivo by reduced sodium phosphate cotransporter type 2 or NaPi-2 expression in the brush border membrane of renal proximal tubules.

Slide 8

Administration of recombinant FGF-23 also reduced serum 1,25 D by suppressing 1-alpha hydroxylase in the kidney. FGF-23 also induces renal 24 hydroxylase to suppress serum 1,25 D. Although the importance of FGF-23 is established in the pathogenesis of phosphate wasting disorders, the manner of regulation of its circulating level is still controvercial. Because of its hypophosphatemic effect, plasma FGF-23 may be regulated by serum phosphate.  So, first of all, we employed uremic patients to examine the role of serum phosphate in FGF-23 regulation.

Slide 9

Plasma FGF-23 levels increased in uremic patients, and more in the patients with maintenance hemodialysis. In the 158 male patients on maintenance hemodialysis who were all anuria, FGF-23 level was significantly correlated positively with inorganic phosphate by simple regression analysis. In addition, serum intact PTH and calcium levels were also positively correlated.

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Multiple regression analyses confirmed that these three factors, inorganic phosphate, intact PTH, and corrected calcium was each independently determinant of plasma FGF-23 in hemodialysis patients.

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In summary, PTH and calcium could be a positive regulators of FGF-23 in addition to serum phosphate in maintenance hemodialysis patients with secondary hyperparathyroidism. Elevated FGF-23 could not affect the serum phosphate, because these patients could not excrete phosphate from their kidneys. Under these condition of hyperphosphatemia, FGF-23 correlated positively to serum phosphate. Other studies reported that 1,25 D is also positive regulator of FGF-23.

Slide 12

Where are the sources of FGF-23? Recently, bone was hypothesized to be a major source. A specific increase of fgf23 gene expression in bone tissue was observed in Hyp mice. Its expressions were also observed in the bone affected fibrous dysplasia of bone with McCune Albright syndrome, indicating bone could be one of major sources of circulating FGF-23.

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To determine the role of local expression of FGF23 in FD tissue on serum phosphate levels, we examined the relationships between FGF23 expression in FD tissue determined by immunohistochemistry. Eight of 16 FD tissues, which exhibited GNAS mutations, revealed positive staining for FGF-23. These evidence indicate that postzygotic activated mutations of GNAS is necessary for the FD tissue formation by mosaic distribution of mutated osteogenic cell lineage, but is not sufficient to elevate FGF23 expression causing generalized osteomalacia with severe renal phosphate wasting. A negative correlation of the intensity of FGF-23 staining with serum inorganic phosphate levels indicated that the expression of FGF23 in focal FD tissues could be a prominent determinant of serum phosphate levels in isolated FD patient. FGF-23 originating from FD tissue may cause hypophosphatemia not only in isolated FD patients but also in the patients with MAS syndrome.

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To assess the effect of parathyroidectomy in primary hyperparathyroidism, we examined on the patients with primary hyperparathyroidism shown here. The patients exhibited typical biochemical hyperparathyroidism. Creatinine clearance were normal in all subjects analyzed.

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Increased plasma FGF-23 were observed in the patients with primary hyperparathyroidism.

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FGF-23 were significantly correlated positively with serum corrected-calcium and intact PTH, and negatively with creatinine clearance and inorganic phosphate, among which creatinine clearance and corrected-calcium were independently associated factors. This data is also concordant with the previous report on the patients with primary hyperparathyroidism.

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In the previous report that FGF-23 did not change by PTX, they collected samples at 6 days after PTX. To assess the rapid changes of serum PTH and calcium levels on FGF-23 regulation, we collected samples on the next day of PTX. In 18 PTX patients, post-operative FGF-23 levels were significantly decreased, when no bisphosphonate or vitamin D analogs were administered. In some patients with increased plasma FGF-23 post-operatively, large amount of calcium gluconate was administered, resulted in higher serum calcium levels after PTX. Interestingly, post-operative plasma FGF-23 were significantly correlated with corrected calcium, which distribute from hypocalcemia to hypercalcemia. These data indicated that serum calcium levels could be a major regulator of plasma FGF-23 when intrinsic PTH was suppressed right after PTX.

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In addition, when no bisphosphonate, vitamin D analogs or calcium gluconate were administered during the study, plasma FGF-23 levels were decreased significantly by 6 h after PTX and the levels were essentially unchanged on the next morning. Serum phosphate increased after PTX but not significantly. Serum 1,25 D did not change significantly during this period. Taken collectively, these data suggest a role for serum calcium in the regulation of plasma FGF-23 levels.

Slide 19

PTH has a major role in the regulation of serum FGF-23 level in both primary and secondary hyperparathyroidism. 

Slide 20

Circulating FGF-23 levels rise as serum phosphate and/or calcium increase above the respective normal lower limits. FGF-23 may have a role to suppress calcium X phosphate product by accelerating urinary phosphate excretion and suppressing vitamin D activation to prevent tissue damages such as ectopic calcifications. Further studies are desirable to elucidate the physiological roles of FGF-23.

Thank you for your attention.