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      α-Klotho levels in girls with central precocious puberty: potential as a diagnostic and monitoring marker

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          Abstract

          Background

          Recent studies suggest a link between the Klotho protein, sex hormones, and insulin-like growth factor-1 (IGF-1), indicating that α-Klotho levels may rise during puberty, including in central precocious puberty (CPP) cases. This study aimed to explore α-Klotho levels in girls with CPP to assess its potential as a diagnostic and monitoring tool for this condition.

          Methods

          In total, 139 girls, comprising 82 patients diagnosed with CPP and 57 healthy prepubertal controls, were enrolled in this study. From March 2020 to May 2023, we assessed both α-Klotho levels and clinical parameters. α-Klotho concentrations were measured using an α-Klotho ELISA kit. For the girls with CPP, we additionally analyzed samples taken 6 months after GnRH agonist treatment.

          Results

          α-Klotho levels were higher in the CPP group compared with the control (CPP group: 2529 ± 999 ng/mL; control group: 1802 ± 675 pg/mL) (P < 0.001), and its level modest decreased after 6 months of GnRH agonist treatment (2147± 789 pg/mL) (P < 0.001). The association between α-Klotho and IGF-1 SDS, follicular stimulating hormone and baseline luteinizing hormone was assessed by partial correlation after adjusting for age, BMI SDS (r= 0.416, p= <0.001; r= 0.261, p= 0.005; r= 0.278, p= 0.002), respectively. Receiver operating characteristic curve analysis identified an α-Klotho cut-off differentiating CPP from controls, with a cut-off of 1914 pg/mL distinguishing girls with CPP from controls with a sensitivity of 69.5% and specificity of 70.2%; the area under the curve was 0.723.

          Conclusion

          The findings of our study are the first step towards deciphering the role of α-Klotho in puberty induction. With additional data and further research, α-Klotho could potentially be utilized as a significant diagnostic and monitoring tool for CPP.

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          Most cited references24

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          Klotho, Aging, and the Failing Kidney

          Klotho has been recognized as a gene involved in the aging process in mammals for over 30 years, where it regulates phosphate homeostasis and the activity of members of the fibroblast growth factor (FGF) family. The α-Klotho protein is the receptor for Fibroblast Growth Factor-23 (FGF23), regulating phosphate homeostasis and vitamin D metabolism. Phosphate toxicity is a hallmark of mammalian aging and correlates with diminution of Klotho levels with increasing age. As such, modulation of Klotho activity is an attractive target for therapeutic intervention in the diseasome of aging; in particular for chronic kidney disease (CKD), where Klotho has been implicated directly in the pathophysiology. A range of senotherapeutic strategies have been developed to directly or indirectly influence Klotho expression, with varying degrees of success. These include administration of exogenous Klotho, synthetic and natural Klotho agonists and indirect approaches, via modulation of the foodome and the gut microbiota. All these approaches have significant potential to mitigate loss of physiological function and resilience accompanying old age and to improve outcomes within the diseasome of aging.
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            New Insights into the Mechanism of Action of Soluble Klotho

            The klotho gene encodes a type I single-pass transmembrane protein that contains a large extracellular domain, a membrane spanning segment, and a short intracellular domain. Klotho protein exists in several forms including the full-length membrane form (mKl) and a soluble circulating form [soluble klotho (sKl)]. mKl complexes with fibroblast growth factor receptors to form coreceptors for FGF23, which allows it to participate in FGF23-mediated signal transduction and regulation of phosphate and calcium homeostasis. sKl is present in the blood, urine, and cerebrospinal fluid where it performs a multitude of functions including regulation of ion channels/transporters and growth factor signaling. How sKl exerts these pleiotropic functions is poorly understood. One hurdle in understanding sKl’s mechanism of action as a “hormone” has been the inability to identify a receptor that mediates its effects. In the body, the kidneys are a major source of sKl and sKl levels decline during renal disease. sKl deficiency in chronic kidney disease makes the heart susceptible to stress-induced injury. Here, we summarize the current knowledge of mKl’s mechanism of action, the mechanistic basis of sKl’s protective, FGF23-independent effects on the heart, and provide new insights into the mechanism of action of sKl focusing on recent findings that sKl binds sialogangliosides in membrane lipid rafts to regulate growth factor signaling.
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              Tissue expression and source of circulating αKlotho.

              αKlotho (Klotho), a type I transmembrane protein and a coreceptor for Fibroblast Growth Factor-23, was initially thought to be expressed only in a limited number of tissues, most importantly the kidney, parathyroid gland and choroid plexus. Emerging data may suggest a more ubiquitous Klotho expression pattern which has prompted reevaluation of the restricted Klotho paradigm. Herein we systematically review the evidence for Klotho expression in various tissues and cell types in humans and other mammals, and discuss potential reasons behind existing conflicting data. Based on current literature and tissue expression atlases, we propose a classification of tissues into high, intermediate and low/absent Klotho expression. The functional relevance of Klotho in organs with low expression levels remain uncertain and there is currently limited data on a role for membrane-bound Klotho outside the kidney. Finally, we review the evidence for the tissue source of soluble Klotho, and conclude that the kidney is likely to be the principal source of circulating Klotho in physiology.
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                Author and article information

                Contributors
                Role: Role: Role:
                URI : https://loop.frontiersin.org/people/2312744Role: Role: Role:
                URI : https://loop.frontiersin.org/people/2236909Role: Role:
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                08 April 2024
                2024
                : 15
                : 1383812
                Affiliations
                [1] 1 Department of Pediatrics, Hallym University College of Medicine , Chuncheon, Republic of Korea
                [2] 2 Department of Pediatrics, Kangdong Sacred Heart Hospital , Seoul, Republic of Korea
                Author notes

                Edited by: Semra Çaglar Çetinkaya, University of Health Sciences, Türkiye

                Reviewed by: Anastasios Serbis, University of Ioannina, Greece

                Paul B. Kaplowitz, Children’s National Hospital, United States

                Ece Bober, Dokuz Eylül University, Türkiye

                *Correspondence: Eu-Seon Noh, bbananet1@ 123456naver.com ; Il Tae Hwang, ithwang83@ 123456kdh.or.kr

                †These authors have contributed equally to this work

                Article
                10.3389/fendo.2024.1383812
                11033302
                38650713
                b06b91d9-d911-46c6-ba6c-f9dd75aa52b4
                Copyright © 2024 Park, Noh and Hwang

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 08 February 2024
                : 25 March 2024
                Page count
                Figures: 2, Tables: 4, Equations: 0, References: 24, Pages: 6, Words: 2413
                Funding
                The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
                Categories
                Endocrinology
                Original Research
                Custom metadata
                Pediatric Endocrinology

                Endocrinology & Diabetes
                α-klotho,igf-1,central precocious puberty,gnrha,puberty
                Endocrinology & Diabetes
                α-klotho, igf-1, central precocious puberty, gnrha, puberty

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