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Bone resorption is regulated by cell-autonomous negative feedback loop of Stat5–Dusp axis in the osteoclast

Signal transducer and activator of transcription 5 (Stat5) is essential for cytokine-regulated processes such as proliferation, differentiation, and survival in hematopoietic cells. To investigate the role of Stat5 in osteoclasts, we generated mice with an osteoclast-specific conditional deletion of...

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Autores principales: Hirose, Jun, Masuda, Hironari, Tokuyama, Naoto, Omata, Yasunori, Matsumoto, Takumi, Yasui, Tetsuro, Kadono, Yuho, Hennighausen, Lothar, Tanaka, Sakae
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3892975/
https://www.ncbi.nlm.nih.gov/pubmed/24367002
http://dx.doi.org/10.1084/jem.20130538
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author Hirose, Jun
Masuda, Hironari
Tokuyama, Naoto
Omata, Yasunori
Matsumoto, Takumi
Yasui, Tetsuro
Kadono, Yuho
Hennighausen, Lothar
Tanaka, Sakae
author_facet Hirose, Jun
Masuda, Hironari
Tokuyama, Naoto
Omata, Yasunori
Matsumoto, Takumi
Yasui, Tetsuro
Kadono, Yuho
Hennighausen, Lothar
Tanaka, Sakae
author_sort Hirose, Jun
collection PubMed
description Signal transducer and activator of transcription 5 (Stat5) is essential for cytokine-regulated processes such as proliferation, differentiation, and survival in hematopoietic cells. To investigate the role of Stat5 in osteoclasts, we generated mice with an osteoclast-specific conditional deletion of Stat5 (Stat5 conditional knockout [cKO] mice) and analyzed their bone phenotype. Stat5 cKO mice exhibited osteoporosis caused by an increased bone-resorbing activity of osteoclasts. The activity of mitogen-activated protein kinases (MAPKs), in particular extracellular signal–related kinase, was increased in Stat5 cKO osteoclasts, whereas the expression of the MAPK phosphatases dual specificity phosphatase 1 (Dusp1) and Dusp2 was significantly decreased. Interleukin-3 (IL-3) stimulated the phosphorylation and nuclear translocation of Stat5 in osteoclasts, and Stat5 expression was up-regulated in response to receptor activator of nuclear factor κB ligand (RANKL). The results suggest that Stat5 negatively regulates the bone-resorbing function of osteoclasts by promoting Dusp1 and Dusp2 expression, and IL-3 promotes Stat5 activation in osteoclasts.
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spelling pubmed-38929752014-07-13 Bone resorption is regulated by cell-autonomous negative feedback loop of Stat5–Dusp axis in the osteoclast Hirose, Jun Masuda, Hironari Tokuyama, Naoto Omata, Yasunori Matsumoto, Takumi Yasui, Tetsuro Kadono, Yuho Hennighausen, Lothar Tanaka, Sakae J Exp Med Article Signal transducer and activator of transcription 5 (Stat5) is essential for cytokine-regulated processes such as proliferation, differentiation, and survival in hematopoietic cells. To investigate the role of Stat5 in osteoclasts, we generated mice with an osteoclast-specific conditional deletion of Stat5 (Stat5 conditional knockout [cKO] mice) and analyzed their bone phenotype. Stat5 cKO mice exhibited osteoporosis caused by an increased bone-resorbing activity of osteoclasts. The activity of mitogen-activated protein kinases (MAPKs), in particular extracellular signal–related kinase, was increased in Stat5 cKO osteoclasts, whereas the expression of the MAPK phosphatases dual specificity phosphatase 1 (Dusp1) and Dusp2 was significantly decreased. Interleukin-3 (IL-3) stimulated the phosphorylation and nuclear translocation of Stat5 in osteoclasts, and Stat5 expression was up-regulated in response to receptor activator of nuclear factor κB ligand (RANKL). The results suggest that Stat5 negatively regulates the bone-resorbing function of osteoclasts by promoting Dusp1 and Dusp2 expression, and IL-3 promotes Stat5 activation in osteoclasts. The Rockefeller University Press 2014-01-13 /pmc/articles/PMC3892975/ /pubmed/24367002 http://dx.doi.org/10.1084/jem.20130538 Text en © 2014 Hirose et al. 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 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Hirose, Jun
Masuda, Hironari
Tokuyama, Naoto
Omata, Yasunori
Matsumoto, Takumi
Yasui, Tetsuro
Kadono, Yuho
Hennighausen, Lothar
Tanaka, Sakae
Bone resorption is regulated by cell-autonomous negative feedback loop of Stat5–Dusp axis in the osteoclast
title Bone resorption is regulated by cell-autonomous negative feedback loop of Stat5–Dusp axis in the osteoclast
title_full Bone resorption is regulated by cell-autonomous negative feedback loop of Stat5–Dusp axis in the osteoclast
title_fullStr Bone resorption is regulated by cell-autonomous negative feedback loop of Stat5–Dusp axis in the osteoclast
title_full_unstemmed Bone resorption is regulated by cell-autonomous negative feedback loop of Stat5–Dusp axis in the osteoclast
title_short Bone resorption is regulated by cell-autonomous negative feedback loop of Stat5–Dusp axis in the osteoclast
title_sort bone resorption is regulated by cell-autonomous negative feedback loop of stat5–dusp axis in the osteoclast
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3892975/
https://www.ncbi.nlm.nih.gov/pubmed/24367002
http://dx.doi.org/10.1084/jem.20130538
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