FGF23 and syndromes of abnormal renal phosphate handling.
FGF23 and syndromes of abnormal renal phosphate handling.
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DOI：
10.1007/978-1-4614-0887-1_3
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发表时间：
2012
影响因子：
--
通讯作者：
Jüppner H
中科院分区：
文献类型：
--
作者：
Bergwitz C;Jüppner H
成纤维细胞生长因子23（FGF 23）是以前未认识到的激素骨-甲状旁腺-肾轴的一部分，其由1，25（OH）2-维生素D（1，25（OH）2D）、饮食和循环磷酸盐以及可能的PTH调节。发现FGF 23是肿瘤中的体液因子，导致低磷酸盐血症和骨软化，并通过鉴定FGF 23的突变形式，导致常染色体显性低磷酸盐血症佝偻病（ADHR），一种罕见的遗传性疾病。FGF 23似乎主要由骨细胞分泌，其中其表达被1，25（OH）2D上调，并且可能被升高的血清磷酸盐水平上调。其合成和分泌通过涉及与X染色体上的内肽酶（PHEX）、牙本质基质蛋白1（DMP 1）和外核苷酸焦磷酸酶/磷酸二酯酶1（ENPP 1）同源的磷酸盐调节基因的未知机制减少。因此，这些基因的功能缺失突变是X连锁或常染色体隐性遗传的低磷血症疾病的基础。由于缺乏UDP-N-乙酰基-α-D-半乳糖胺：多肽N-乙酰基半乳糖胺转移酶3（GALNT 3）或由于某些纯合FGF 23突变导致FGF 23的O-糖基化受损，导致完整FGF 23分泌减少，并导致家族性低血磷肿瘤性钙质沉着症。FGF 23通过FGF受体和辅助受体Klotho起作用，以减少肾脏中的1，25（OH）2D合成，并可能减少甲状旁腺合成甲状旁腺激素（PTH）。它还与PTH协同作用，通过减少近端小管中钠-磷酸盐协同转运蛋白NaPi-IIa和NaPi-IIc的表达来增加肾磷酸盐排泄。这两种转运蛋白的功能缺失突变分别导致常染色体隐性范可尼综合征或遗传性低磷血症性佝偻病伴高钙尿症。
Fibroblast growth factor 23 (FGF23) is part of a previously unrecognized hormonal bone-parathyroid-kidney axis, which is modulated by 1,25(OH)2-vitamin D (1,25(OH)2D), dietary and circulating phosphate and possibly PTH. FGF23 was discovered as the humoral factor in tumors that causes hypophosphatemia and osteomalacia and through the identification of a mutant form of FGF23 that leads to autosomal dominant hypophosphatemic rickets (ADHR), a rare genetic disorder. FGF23 appears to be mainly secreted by osteocytes where its expression is up-regulated by 1,25(OH)2D and probably by increased serum phosphate levels. Its synthesis and secretion is reduced through yet unknown mechanisms that involve the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX), dentin matrix protein 1 (DMP1) and ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). Consequently, loss-of-function mutations in these genes underlie hypophosphatemic disorders that are either X-linked or autosomal recessive. Impaired O-glycosylation of FGF23 due to the lack of UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyl-transferase 3 (GALNT3) or due to certain homozygous FGF23 mutations results in reduced secretion of intact FGF23 and leads to familial hypophosphatemic tumoral calcinosis. FGF23 acts through FGF-receptors and the coreceptor Klotho to reduce 1,25(OH)2D synthesis in the kidney and probably the synthesis of parathyroid hormone (PTH) by the parathyroid glands. It furthermore synergizes with PTH to increase renal phosphate excretion by reducing expression of the sodium-phosphate cotransporters NaPi-IIa and NaPi-IIc in the proximal tubules. Loss-of-function mutations in these two transporters lead to autosomal recessive Fanconi syndrome or to hereditary hypophosphatemic rickets with hypercalciuria, respectively.