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Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts

Insulin receptor substrates (IRS-1 and IRS-2) are essential for intracellular signaling by insulin and insulin-like growth factor-I (IGF-I), anabolic regulators of bone metabolism. Although mice lacking the IRS-2 gene (IRS-2 (−/−) mice) developed normally, they exhibited osteopenia with decreased bo...

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Autores principales: Akune, Toru, Ogata, Naoshi, Hoshi, Kazuto, Kubota, Naoto, Terauchi, Yasuo, Tobe, Kazuyuki, Takagi, Hideko, Azuma, Yoshiaki, Kadowaki, Takashi, Nakamura, Kozo, Kawaguchi, Hiroshi
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2002
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173484/
https://www.ncbi.nlm.nih.gov/pubmed/12379806
http://dx.doi.org/10.1083/jcb.200204046
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author Akune, Toru
Ogata, Naoshi
Hoshi, Kazuto
Kubota, Naoto
Terauchi, Yasuo
Tobe, Kazuyuki
Takagi, Hideko
Azuma, Yoshiaki
Kadowaki, Takashi
Nakamura, Kozo
Kawaguchi, Hiroshi
author_facet Akune, Toru
Ogata, Naoshi
Hoshi, Kazuto
Kubota, Naoto
Terauchi, Yasuo
Tobe, Kazuyuki
Takagi, Hideko
Azuma, Yoshiaki
Kadowaki, Takashi
Nakamura, Kozo
Kawaguchi, Hiroshi
author_sort Akune, Toru
collection PubMed
description Insulin receptor substrates (IRS-1 and IRS-2) are essential for intracellular signaling by insulin and insulin-like growth factor-I (IGF-I), anabolic regulators of bone metabolism. Although mice lacking the IRS-2 gene (IRS-2 (−/−) mice) developed normally, they exhibited osteopenia with decreased bone formation and increased bone resorption. Cultured IRS-2 (−) (/) (−) osteoblasts showed reduced differentiation and matrix synthesis compared with wild-type osteoblasts. However, they showed increased receptor activator of nuclear factor κB ligand (RANKL) expression and osteoclastogenesis in the coculture with bone marrow cells, which were restored by reintroduction of IRS-2 using an adenovirus vector. Although IRS-2 was expressed and phosphorylated by insulin and IGF-I in both osteoblasts and osteoclastic cells, cultures in the absence of osteoblasts revealed that intrinsic IRS-2 signaling in osteoclastic cells was not important for their differentiation, function, or survival. It is concluded that IRS-2 deficiency in osteoblasts causes osteopenia through impaired anabolic function and enhanced supporting ability of osteoclastogenesis. We propose that IRS-2 is needed to maintain the predominance of bone formation over bone resorption, whereas IRS-1 maintains bone turnover, as we previously reported; the integration of these two signalings causes a potent bone anabolic action by insulin and IGF-I.
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spelling pubmed-21734842008-05-01 Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts Akune, Toru Ogata, Naoshi Hoshi, Kazuto Kubota, Naoto Terauchi, Yasuo Tobe, Kazuyuki Takagi, Hideko Azuma, Yoshiaki Kadowaki, Takashi Nakamura, Kozo Kawaguchi, Hiroshi J Cell Biol Article Insulin receptor substrates (IRS-1 and IRS-2) are essential for intracellular signaling by insulin and insulin-like growth factor-I (IGF-I), anabolic regulators of bone metabolism. Although mice lacking the IRS-2 gene (IRS-2 (−/−) mice) developed normally, they exhibited osteopenia with decreased bone formation and increased bone resorption. Cultured IRS-2 (−) (/) (−) osteoblasts showed reduced differentiation and matrix synthesis compared with wild-type osteoblasts. However, they showed increased receptor activator of nuclear factor κB ligand (RANKL) expression and osteoclastogenesis in the coculture with bone marrow cells, which were restored by reintroduction of IRS-2 using an adenovirus vector. Although IRS-2 was expressed and phosphorylated by insulin and IGF-I in both osteoblasts and osteoclastic cells, cultures in the absence of osteoblasts revealed that intrinsic IRS-2 signaling in osteoclastic cells was not important for their differentiation, function, or survival. It is concluded that IRS-2 deficiency in osteoblasts causes osteopenia through impaired anabolic function and enhanced supporting ability of osteoclastogenesis. We propose that IRS-2 is needed to maintain the predominance of bone formation over bone resorption, whereas IRS-1 maintains bone turnover, as we previously reported; the integration of these two signalings causes a potent bone anabolic action by insulin and IGF-I. The Rockefeller University Press 2002-10-14 /pmc/articles/PMC2173484/ /pubmed/12379806 http://dx.doi.org/10.1083/jcb.200204046 Text en Copyright © 2002, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Akune, Toru
Ogata, Naoshi
Hoshi, Kazuto
Kubota, Naoto
Terauchi, Yasuo
Tobe, Kazuyuki
Takagi, Hideko
Azuma, Yoshiaki
Kadowaki, Takashi
Nakamura, Kozo
Kawaguchi, Hiroshi
Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts
title Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts
title_full Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts
title_fullStr Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts
title_full_unstemmed Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts
title_short Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts
title_sort insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173484/
https://www.ncbi.nlm.nih.gov/pubmed/12379806
http://dx.doi.org/10.1083/jcb.200204046
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