title: The aging suppressor klotho: a potential regulator of growth hormone secretion.
abstract: Klotho is a transmembranal protein highly expressed in the kidneys, choroid plexus, and anterior pituitary. Klotho can also be cleaved and shed and acts as a circulating hormone. Klotho-deficient mice (kl/kl mice) develop a phenotype resembling early aging. Several lines of evidence suggest a role for klotho in the regulation of growth hormone (GH) secretion. The kl/kl mice are smaller compared with their wild-type counterparts, and their somatotropes show reduced numbers of secretory granules. Moreover, klotho is a potent inhibitor of the IGF-I pathway, a negative regulator of GH secretion. Therefore, we hypothesized that klotho may enhance GH secretion. The effect of klotho on GH secretion was examined in GH3 rat somatotrophs, cultured rat pituitaries, and cultured human GH-secreting adenomas. In all three models, klotho treatment increased GH secretion. Prolonged treatment of mice with intraperitoneal klotho injections increased mRNA levels of IGF-I and IGF-I-binding protein-3 mRNA in the liver, reflecting increased serum GH levels. In accord with its ability to inhibit the IGF-I pathway, klotho partially restored the inhibitory effect of IGF-I on GH secretion. Klotho is known to be a positive regulator of basic bFGF signaling. We studied rat pituitaries and human adenoma cultures and noted that bFGF increased GH secretion and stimulated ERK1/2 phosphorylation. Both effects were augmented following treatment with klotho. Taken together, our data indicate for the first time that klotho is a positive regulator of GH secretion and suggest the IGF-I and bFGF pathways as potential mediators of this effect.
authors.affiliation: Institute of Oncology, 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: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Felsenstein Medical Research Center, Rabin Medical Center, Petach Tiqva, Israel; and.
authors.forename: Hadara
authors.initials: H
authors.lastname: Rubinfeld
authors.affiliation: Institute of Oncology, 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; Department of Neurosurgery, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Zvi R
authors.initials: ZR
authors.lastname: Cohen
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Neurosurgery, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Hadani
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Felsenstein Medical Research Center, Rabin Medical Center, Petach Tiqva, Israel; and.
authors.forename: Ilan
authors.initials: I
authors.lastname: Shimon
authors.affiliation: Institute of Oncology, Sourasky Medical Center, Tel Aviv, Israel; rubinekt@gmail.com.
authors.forename: Tami
authors.initials: T
authors.lastname: Rubinek
mesh_terms: D000236:Adenoma / Q000378:metabolism / Q000473:pathology; D000375:Aging; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism*; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000090265:Klotho Proteins; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D052683:Somatotrophs / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: acromegaly; basic fibroblast growth factor; extracellular signal-regulated kinase; growth hormone; insulin-like growth factor I; klotho; pituitary