2007 Fiscal Year Final Research Report Summary
Interaction of signals between klotho and insulin in ageing and the related disorders
| Project/Area Number |
17390411
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Orthopaedic surgery
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| Research Institution | The University of Tokyo |
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Principal Investigator |
KARITA Tatsuro The University of Tokyo, Faculty of Medicine, Lecturer (80359611)
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| Co-Investigator(Kenkyū-buntansha) |
OGATA Naoshi The University of Tokyo, Faculty of Medicine, Visiting Faculty Member (10361495)
HARA Yukinori The University of Tokyo, Faculty of Medicine, Research Associate (30396741)
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| Project Period (FY) |
2005 – 2007
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| Keywords | klotho / insulin / ageing / bone |
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| Research Abstract |
Klotho and insulin/IGF-I has been reported to be the principal signals in ageing and the related disorders. The present project sought to examine the interaction of the two signals in ageing and a representative age-related disorder osteoporosis.
We previously reported that a defect in Klotho gene expression leads to a syndrome that may resemble premature aging. In the present project, we found that overexpression of Klotho can extend life span, and we suggest that Klotho functions as an aging suppressor gene in mammals. We further found that the extracellular domain of Klotho protein circulates in the blood and binds to a putative cell-surface receptor. Klotho has marked effects on insulin physiology, apparently because it suppresses tyrosine phosphorylation of insulin and IGF1 receptors, which results in reduced activity of IRS proteins and their association with P13-kinase, thereby inhibiting insulin and IGF1 signaling. Extended life span upon negative regulation of insulin and IGF1 signaling is an evolutionarily conserved mechanism to suppress aging. Klotho appears to be a peptide hormone to modulate such signaling and thereby mediate insulin metabolism and aging.
Contrarily our in vivo and in vitro examinations failed to find the interaction between the two signals with age-related bone metabolism. These indicate that the two signals interact each other during systemic ageing process, although they have distinct mechanism of regulation of bone remodeling.
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Author(s)
Kawamura N, Kugimiya F, Oshima Y, Ohba S, Ikeda T, Saito T, Shinoda Y, Kawasaki Y, Ogata N, Hoshi K, Akiyama T, Chen WS, Hay N, Tobe T, Kadowaki T, Azuma Y, Tanaka S, Nakamura K, Chung UI, Kawaguchi H
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[Journal Article] Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability. Runx2 contributes to pathogenesis of osteoarthritis in mice after induction of knee joint instability2006
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Kamekura S, Kawasaki Y, Hoshi K, Shimoaka T, Chikuda H, Maruyama Z, Komori T, Sato S, Takeda S, Karsenty G, Nakamura K, Chung UI, Kawaguchi H
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Arthritis Rheum 54
Pages: 2462-2470
Description
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[Journal Article] Regulation of bone formation by adiponectin through autocrine/paracrine and endocrine pathways2006
Author(s)
Shinoda Y, Yamaguchi M, Ogata N, Akune T, Kubota N, Yamauchi T, Terauchi Y, Kadowaki T, Takeuchi Y, Fukumoto S, Ikeda T, Hoshi K, Chung UI, Nakamura K, Kawaguchi H
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Journal Title
J Cell Biochem 99
Pages: 196-208
Description
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[Journal Article] Klotho insufficiency causes decrease of ribosomal RNA gene transcription activity, cytoplasmic RNA and rough ER in the spinal anterior horn cells2005
Author(s)
Anamizu Y, Kawaguchi H, Seichi A, Yamaguchi S, Kawakami E, Kanda N, Matsubara S, Kuro-o M, Nabeshima Y, Nakamura K, Oyanagi K
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Journal Title
Acta Neuropathol 109
Pages: 457-466
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Insulin receptor substrate-1 is required for bone anabolic function of parathyroid hormone in mice2005
Author(s)
Yamaguchi M, Ogata N, Shinoda Y, Akune T, Kamekura S, Terauchi Y, Kadowaki T, Hoshi K, Chung UI, Nakamura K, Kawaguchi H
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Journal Title
Endocrinology 146
Pages: 2620-2628
Description
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[Journal Article] Osteoarthritis development in novel experimental mouse models induced by knee joint instability2005
Author(s)
Kamekura S, Hoshi K, Shimoaka T, Chung UI, Chikuda H, Yamada T, Uchida M, Ogata N, Seichi A, Nakamura K, Kawaguchi H
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Journal Title
Osteoarthritis Cartilage 13
Pages: 632-641
Description
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[Journal Article] Suppression of aging in mice by the hormone Klotho2005
Author(s)
Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gumani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M
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Journal Title
Mech Ageing Dev 126
Pages: 1274-1283
Description
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