title: Klotho response to treatment with growth hormone and the role of IGF-I as a mediator.
abstract: BACKGROUND
  Klotho is an aging-modulating protein expressed mainly in the kidneys, which can be cleaved and shed to act as a circulating hormone. Several lines of evidence suggest a tight interaction between klotho and the GH-IGF-I axis. We showed previously that klotho levels are decreased in pediatric patients with growth hormone deficiency (GHD). Our aim now is to investigate the effect of GH therapy on klotho levels in these patients and to elucidate the role of IGF-1 in mediating secretion of klotho.
  
  
  METHODS
  Klotho levels were measured in 29 GHD pediatric patients (males=15, aged 12.2±3.3years), treated with GH for 2.5±2.8years; nineteen patients had samples obtained both before and during treatment. The effect of IGF-I and its downstream effectors on secretion of klotho to media was studied in COS-7 cells overexpressing klotho.
  
  
  RESULTS
  Klotho levels increased under GH treatment (from 1321±691pg/ml to 3380±2120pg/ml, p<0.001), and were higher compared to controls (1645±778pg/ml, p<0.001), resulting in supraphysiological levels. Fold-increase in klotho correlated with fold-increase in IGF-I (r=0.63, p=0.004). Studies in COS-7 cells overexpressing klotho revealed mTOR-dependent induction of klotho shedding by IGF-I.
  
  
  CONCLUSIONS
  Klotho levels increased during GH treatment of pediatric GHD patients. This increase was associated with an increase in IGF-I levels. Furthermore, we showed, for the first time, a direct role of IGF-I in the regulation of klotho's shedding which depends on activation of the AKT-mTOR pathway. Our findings add further support for the close association between klotho and the GH/IGF-I axis.
authors.affiliation: Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Tami
authors.initials: T
authors.lastname: Rubinek
authors.affiliation: Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shiri
authors.initials: S
authors.lastname: Shahmoon
authors.affiliation: Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Shabtay-Orbach
authors.affiliation: Pediatric Endocrinology and Diabetes Unit, The Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Ben Ami
authors.affiliation: Pediatric Endocrinology and Diabetes Unit, The Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Levy-Shraga
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Endocrinology and Diabetes Unit, The Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel.
authors.forename: Kineret
authors.initials: K
authors.lastname: Mazor-Aronovitch
authors.affiliation: Pediatric Endocrinology and Diabetes Unit, The Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel.
authors.forename: Yonatan
authors.initials: Y
authors.lastname: Yeshayahu
authors.affiliation: lnstitute of Chemical Pathology, Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel.
authors.forename: Ram
authors.initials: R
authors.lastname: Doolman
authors.affiliation: Institute of Endocrinology, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel.
authors.forename: Rina
authors.initials: R
authors.lastname: Hemi
authors.affiliation: Institute of Endocrinology, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel.
authors.forename: Hannah
authors.initials: H
authors.lastname: Kanety
authors.affiliation: Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ido
authors.initials: I
authors.lastname: Wolf
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Endocrinology and Diabetes Unit, The Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel. Electronic address: dmodan@sheba.health.gov.il.
authors.forename: Dalit
authors.initials: D
authors.lastname: Modan-Moses
mesh_terms: D000293:Adolescent; D000375:Aging; D000818:Animals; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D005260:Female; D005966:Glucuronidase / Q000378:metabolism*; D019382:Human Growth Hormone / Q000172:deficiency* / Q000627:therapeutic use*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000187:drug effects*; D000090265:Klotho Proteins; D008297:Male; D017510:Protein Folding
chemical_list: D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: Growth hormone; Growth hormone deficiency; IGF-I; Klotho; mTOR