Division of Endocrinology and Diabetology, University Hospital Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland Department of Neurosurgery, University Hospital Zurich, Frauenklinikstrasse 10, 8091 Zurich, Switzerland Division of Endocrinology and Diabetology, Kantonsspital St Gallen, 9007 St Gallen, Switzerland Department of Neurosurgery, Clinic Hirslanden, Witellikerstrasse 40, 8032 Zurich, Switzerland.
J Endocrinol. 2013 Nov 1;219(2):R37-57. doi: 10.1530/JOE-13-0285. Print 2013 Nov.
Acromegaly is characterized by excessively high GH and IGF1 levels. Recent data suggest that soluble Klotho (sKlotho) is also elevated in patients with active acromegaly. sKlotho decreases towards normal following removal of the GH-producing pituitary adenoma. The Klotho gene was identified in mice following its accidental disruption by ectopic DNA. It is an ageing suppressor gene of restricted expression (mainly in kidneys, brain, and parathyroid and pituitary glands) encoding a transmembrane protein, mKlotho. mKlotho serves as a co-receptor in fibroblast growth factor 23 (FGF23) signalling. FGF23 promotes urinary phosphate excretion and inhibits the synthesis of calcitriol. The ectodomain of mKlotho is enzymatically released to result in a humoral factor, sKlotho, which exerts systemic effects (on ion channels and signalling pathways), possibly by working as an enzyme that modifies glycans of cell surface glycoproteins. GH enhances renal phosphate reabsorption and calcitriol production, i.e. exerts effects in the proximal tubule opposing those attributed to mKlotho, and attenuates calciuria in the distal tubule similar to sKlotho. sKlotho can be measured in extracellular fluids (serum, urine and cerebrospinal fluid (CSF)) by an ELISA. In line with predominant expression of Klotho in kidneys and choroid plexus, concentrations of sKlotho are particularly high in urine and CSF. Determination of sKlotho in serum and urine (both presumably reflecting GH action on the kidneys) could be used as a supplementary tool in the diagnosis and follow-up of patients with acromegaly. The question arises whether GH exerts selected actions via modifying activities of Klotho.
肢端肥大症的特征是生长激素 (GH) 和胰岛素样生长因子 1 (IGF1) 水平过高。最近的数据表明，活性肢端肥大症患者的可溶性 Klotho（sKlotho）水平也升高。切除产生 GH 的垂体腺瘤后，sKlotho 水平下降至正常。Klotho 基因是在其通过异位 DNA 意外破坏后在小鼠中被鉴定出来的。它是一种表达受限的衰老抑制基因（主要在肾脏、大脑、甲状旁腺和垂体中），编码一种跨膜蛋白 mKlotho。mKlotho 作为成纤维细胞生长因子 23 (FGF23) 信号转导的辅助受体。FGF23 促进尿磷酸盐排泄并抑制 1,25-二羟维生素 D3（calcitriol）的合成。mKlotho 的外显子酶解释放出一种体液因子 sKlotho，它发挥全身作用（对离子通道和信号通路），可能通过作为一种修饰细胞表面糖蛋白聚糖的酶发挥作用。GH 增强肾脏磷酸盐重吸收和 calcitriol 生成，即在近端肾小管中发挥与 mKlotho 相反的作用，并减弱远曲小管中的钙尿，类似于 sKlotho。sKlotho 可通过 ELISA 在细胞外液（血清、尿液和脑脊液 (CSF)) 中测量。与 Klotho 在肾脏和脉络丛中的主要表达一致，sKlotho 的浓度在尿液和 CSF 中特别高。血清和尿液中 sKlotho 的测定（两者都可能反映 GH 对肾脏的作用）可作为肢端肥大症患者诊断和随访的辅助工具。问题是 GH 是否通过修饰 Klotho 的活性来发挥其选择作用。
