Klotho Lacks an FGF23‐Independent Role in Mineral Homeostasis

Fibroblast growth factor‐23 (FGF23) is a bone‐derived hormone regulating vitamin D hormone production and renal handling of minerals by signaling through an FGF receptor/αKlotho (Klotho) receptor complex. Whether Klotho has FGF23‐independent effects on mineral homeostasis is a controversial issue. Here, we aimed to shed more light on this controversy by comparing male and female triple knockout mice with simultaneous deficiency in Fgf23 and Klotho and a nonfunctioning vitamin D receptor (VDR) (Fgf23/Klotho/VDR) with double (Fgf23/VDR, Klotho/VDR, and Fgf23/Klotho) and single Fgf23, Klotho, and VDR mutants. As expected, 4‐week‐old Fgf23, Klotho, and Fgf23/Klotho knockout mice were hypercalcemic and hyperphosphatemic, whereas VDR, Fgf23/VDR, and Klotho/VDR mice on rescue diet were normocalcemic and normophosphatemic. Serum levels of calcium, phosphate, and sodium did not differ between 4‐week‐old triple Fgf23/Klotho/VDR and double Fgf23/VDR or Klotho/VDR knockout mice. Notably, 3‐month‐old Fgf23/Klotho/VDR triple knockout mice were indistinguishable from double Fgf23/VDR and Klotho/VDR compound mutants in terms of serum calcium, serum phosphate, serum sodium, and serum PTH, as well as urinary calcium and sodium excretion. Protein expression analysis revealed increased membrane abundance of sodium‐phosphate co‐transporter 2a (NaPi‐2a), and decreased expression of sodium‐chloride co‐transporter (NCC) and transient receptor potential cation channel subfamily V member 5 (TRPV5) in Fgf23/Klotho/VDR, Fgf23/VDR, and Klotho/VDR mice, relative to wild‐type and VDR mice, but no differences between triple and double knockouts. Further, ex vivo treatment of live kidney slices isolated from wild‐type and Klotho/VDR mice with soluble Klotho did not induce changes in intracellular phosphate, calcium or sodium accumulation assessed by two‐photon microscopy. In conclusion, our data suggest that the main physiological function of Klotho for mineral homeostasis in vivo is its role as co‐receptor mediating Fgf23 action. © 2017 American Society for Bone and Mineral Research.     

KLOTHO基因C-1818T多态性与中国苏皖地区汉族人群急性冠脉综合征的相关性分析

目的:探讨KLOTHO基因第4外显子C-1818T多态性与中国苏皖地区汉族人群急性冠状动脉综合征(acute coronary syndrome,ACS)的可能关系?方法:应用聚合酶链反应(polymerase chain reaction,PCR)及基因芯片(gene microarray)技术对375例ACS患者(ACS组)和235例经相关检查排除冠心病(CAD)者(对照组)进行KLOTHO基因C-1818T多态性的检测?结果:与对照组相比:①ACS患者CC?CT和TT基因型以及T等位基因型频率分布无显著差异;②老年人(≥60岁)?男性和老年男性ACS患者的CT基因型频率均明显升高(P值分别为0.031?0.035和0.041)?在调整相关危险因素并经多元Logistic回归分析后,CT基因型与老年人和老年男性ACS均存在相关关系(P值分别为0.010和0.047),与男性ACS无明显相关关系(P=0.103)?结论:在中国苏皖地区汉族人群中,KLOTHO基因C-1818T多态性CT基因型与老年和老年男性ACS的发病均存在相关性?     

Association of KLOTHO gene polymorphisms with knee osteoarthritis in Greek population

Based on the fact that klotho‐deficient mice exhibit multiple aging phenotypes, including osteopenia and subchondral sclerosis of joints and on the recent observation that KLOTHO gene plays an important role in calcium/phosphate homeostasis, we explored the possibility whether human KLOTHO gene polymorphisms are associated with osteoarthritis (OA). A total of 752 individuals participated in the study. The knee OA group consisted of 369 patients; 298 women (mean age 65.9 ± 8.2; range 40–92 years) and 71 men (mean age 65.7 ± 9.1; range 30–82 years). The control population consisted of 383 subjects; 231 women (mean age 65.8 ± 8.4; range 35–90 years) and 152 men (mean age 61.5 ± 9.3; range 28–87 years). Four SNPs—G395A in the promoter region, G1110C in exon 2, C1818T and C2298T in exon 4—were genotyped. A significant genotypic and allelic association was observed in SNP C2998T and knee OA, while genotype GA of SNP G395A was significantly associated (p = 0.039) with knee OA in females only. For the first time, an association was observed between SNPs G395A and C2998T of the KLOTHO gene and knee osteoarthritis implicating KLOTHO in OA pathogenesis. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:1466–1470, 2008     

老年急性冠脉综合征患者KLOTHO基因C-1818T多态性分析

目的:观察中国苏皖地区汉族老年(≥60岁)人群KLOTHO基因第4外显子C-1818T多态性分布,探讨其与老年人急性冠脉综合征(ACS)的可能关系。方法:采用聚合酶链反应及基因芯片技术,检测272例老年ACS患者(ACS组)和139例老年非冠心病者(对照组)的KLOTHO基因C-1818T多态性。结果:(1)与对照组相比:ACS组CT基因型频率明显升高,差异有统计学意义(30.9vs20.9,P=0.031),CC、TT基因型及T等位基因频率差异均无统计学意义(分别为72.7vs65.4、6.5vs3.7和16.9vs19.1,P值均>0.05)。(2)将ACS组按性别进行进一步分析后发现,分别与对照组相比:①男性CT基因型频率明显升高,差异有统计学意义(28.5vs16.7,P=0.041),CC、TT基因型及T等位基因频率差异无统计学意义(分别为75.6vs68.5、7.7vs3.0和16.0vs17.3,P值均>0.05);②女性CC、CT、TT基因型及T等位基因频率差异无统计学意义(分别为68.9vs56.9、26.2vs37.5、4.9vs5.6和18.0vs24.3,P值均>0.05)。在调整相关...     

The relevance of α-KLOTHO to the central nervous system: Some key questions

α-Klotho is well described as an anti-aging protein, with critical roles in kidney function as a transmembrane co-receptor for FGF23, and as a soluble factor in serum. α-Klotho is also expressed in the choroid plexus, where it is released into the cerebrospinal fluid. Nonetheless, α-Klotho is also expressed in the brain parenchyma. Accumulating evidence indicates that this pool of α-Klotho, which we define as brain α-Klotho, may play important roles as a neuroprotective factor and in promoting myelination, thereby supporting healthy brain aging. Here we summarize what is known about brain α-Klotho before focusing on the outstanding scientific questions related to its function. We believe there is a need for in vitro studies designed to distinguish between brain α-Klotho and other pools of α-Klotho, and for a greater understanding of the basic function of soluble α-Klotho. The mechanism by which the human KL-VS variant affects cognition also requires further elucidation. To help address these questions we suggest some experimental approaches that other laboratories might consider. In short, we hope to stimulate fresh ideas and encourage new research approaches that will allow the importance of α-Klotho for the aging brain to become clear.     

中国苏皖地区汉族人群KLOTHO基因启动子G-395A多态性与ACS相关性分析

目的:探讨KLOTHO基因启动子区G-395A多态性与中国苏皖地区汉族人群急性冠脉综合征(acute coronary syndrome,ACS)的关系?方法:采用聚合酶链反应和基因芯片方法对326例ACS(ACS组)[分为亚组急性心肌梗死(acute myocardial infarction,AMI)组和不稳定性心绞痛(unstable angina pectoris,UAP)组]和219例经检查排除冠心病的对照组进行KLOTHO基因G-395A多态性分析?结果:与对照组相比,ACS组?AMI组和UAP组(包括不同年龄和不同性别的亚组)的GG?GA?AA基因型和A等位基因频率均无明显差异(P > 0.05)?结论:KLOTHO基因G-395A多态性与中国苏皖地区汉族人群ACS的发病无显著相关性?     

Xeno‐Klotho Inhibits Parathyroid Hormone Signaling

Although fibroblast growth factor (FGF) 23 was recently identified as a phosphatonin that influences vitamin D metabolism, the underlying signaling mechanisms remain unclear. FGF23 elevates the renal levels of membrane‐associated klotho as well as soluble klotho. Klotho is expressed on distal tubules. Upon enzymatic cleavage, soluble klotho is released into the renal interstitial space and then into the systemic circulation. The expression of 25‐hydroxyvitamin D₃ 1α‐hydroxylase (1‐OH) on proximal tubular cells is controlled by parathyroid hormone (PTH). Klotho binds to various membrane proteins to alter their function. Here, the interaction between the PTH receptor and klotho was studied using various approaches, including immunoprecipitation, in vitro cell culture, and in vivo animal experiments. Immunoprecipitation studies demonstrate, for the first time, that recombinant human klotho protein interacts with human PTH receptors to inhibit the binding of human PTH. Furthermore, when applied to human proximal tubular cells, recombinant human klotho suppresses PTH‐stimulated generation of inositol trisphosphate in vitro. Moreover, PTH‐induced increase of cyclic AMP secretion and 1α,25‐dihydroxyvitamin D₃ (1,25VD) was attenuated by recombinant human klotho in vivo. In addition, recombinant human klotho inhibits the expression of 1‐OH by PTH both in vitro and in vivo. These results suggest that free klotho mediates the FGF23‐induced inhibition of 1,25VD synthesis. © 2015 American Society for Bone and Mineral Research.