Physiological and pathological involvement of FGF-23 in mineral metabolism in human

1) FGF-23基因突变参与肿瘤钙质沉着症我们在家族性肿瘤钙质沉着症患者中发现了FGF-23基因突变。发现错义突变。在哺乳动物细胞中表达突变的FGF-23基因导致FGF-23蛋白显著降解，培养基中基本没有全长和活性的FGF-23。尽管FGF-23的降解产物在循环血液中积累，但我们评估的肿瘤钙质沉积患者的血清中几乎检测不到全长FGF-23的水平。这些数据表明，人体内FGF-23功能丧失导致肿瘤性钙化症，表现为高磷血症和高血清1,25-二羟基维生素d水平。2)健康志愿者血液中FGF-23对血清磷酸盐水平急性升高的反应静脉输注磷酸二钾使血清磷酸盐水平升高至6.0 mg/dl，实验后6小时内循环中FGF-23水平无显著变化。这一结果表明，与高钙血症时甲状旁腺激素分泌迅速减少相反，FGF-23的分泌对血清磷酸盐水平的急性变化没有反应。调节血清FGF-23水平的生理机制有待进一步研究。3)肢端肥大症患者垂体手术前后血清磷酸盐和FGF-23水平肢端肥大症患者血清磷酸盐水平较高，手术成功后正常下降。分析连续17例肢端肥大症患者的临床实验室资料，血清FGF-23水平也随垂体手术而降低。这表明FGF-23的分泌对人体血清磷酸盐水平的降低有迅速的反应。

1) Mutation of FGF-23 gene involved in tumoral calcinosisWe identified mutation of FGF-23 gene in patients with familial tumoral calcinosis. Missense mutation was found. Expression the mutated FGF-23 gene in mammalian cells resulted in remarkable degradation of FGF-23 protein with essentially no full-length and active FGF-23 in culture media. Serum level of full-length FGF-23 was almost undetectable in patients with tumoral calcinossis we evaluated, although degradation products of FGF-23 were accumulated in circulating blood. These data indicate that loss of function of FGF-23 in human causes tumoral calcinosis that presents hyperphosphatemia and high serum level of 1,25-dihydroxyvitamin D.2) Response of circulating FGF-23 to acute increase in serum phosphate level in healthy volunteersWhen serum phosphate level was increased with intravenous infusion of dibasic potassium phosphate to 6.0 mg/dl, circulating level of FGF-23 did not change significantly within 6 hours of experiments. This result suggests that in contrast to rapid decrease in PTH secretion in response to hypercalcemia, secretion of FGF-23 cannot respond to acute changes of serum phosphate level. Physiological mechanisms for regulation of serum FGF-23 level are to be explored with further studies.3) Serum phosphate and FGF-23 levels in patients with acromegaly before and after pituitary surgerySerum phosphate level is higher in patients with acromegaly and decreases normally after successful surgery. When clinical laboratory data of consecutive 17 patients with acromegaly were analyzed, serum level of FGF-23 also concomitantly decreased with pituitary surgery. This indicates secretion of FGF-23 promptly responds to the decrease in serum phosphate level in human.