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The Large Zinc Finger Protein ZAS3 Is a Critical Modulator of Osteoclastogenesis

BACKGROUND: Mice deficient in the large zinc finger protein, ZAS3, show postnatal increase in bone mass suggesting that ZAS3 is critical in the regulation of bone homeostasis. Although ZAS3 has been shown to inhibit osteoblast differentiation, its role on osteoclastogenesis has not been determined....

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Autores principales: Liu, Shujun, Madiai, Francesca, Hackshaw, Kevin V., Allen, Carl E., Carl, Joseph, Huschart, Emily, Karanfilov, Chris, Litsky, Alan, Hickey, Christopher J., Marcucci, Guido, Huja, Sarandeep, Agarwal, Sudha, Yu, Jianhua, Caligiuri, Michael A., Wu, Lai-Chu
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048431/
https://www.ncbi.nlm.nih.gov/pubmed/21390242
http://dx.doi.org/10.1371/journal.pone.0017161
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author Liu, Shujun
Madiai, Francesca
Hackshaw, Kevin V.
Allen, Carl E.
Carl, Joseph
Huschart, Emily
Karanfilov, Chris
Litsky, Alan
Hickey, Christopher J.
Marcucci, Guido
Huja, Sarandeep
Agarwal, Sudha
Yu, Jianhua
Caligiuri, Michael A.
Wu, Lai-Chu
author_facet Liu, Shujun
Madiai, Francesca
Hackshaw, Kevin V.
Allen, Carl E.
Carl, Joseph
Huschart, Emily
Karanfilov, Chris
Litsky, Alan
Hickey, Christopher J.
Marcucci, Guido
Huja, Sarandeep
Agarwal, Sudha
Yu, Jianhua
Caligiuri, Michael A.
Wu, Lai-Chu
author_sort Liu, Shujun
collection PubMed
description BACKGROUND: Mice deficient in the large zinc finger protein, ZAS3, show postnatal increase in bone mass suggesting that ZAS3 is critical in the regulation of bone homeostasis. Although ZAS3 has been shown to inhibit osteoblast differentiation, its role on osteoclastogenesis has not been determined. In this report we demonstrated the role of ZAS3 in bone resorption by examining the signaling mechanisms involved in osteoclastogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Comparison of adult wild-type and ZAS3 knockout (ZAS3−/−) mice showed that ZAS3 deficiency led to thicker bones that are more resistant to mechanical fracture. Additionally, ZAS3−/− bones showed fewer osteoclasts and inefficient M-CSF/sRANKL-mediated osteoclastogenesis ex vivo. Utilizing RAW 264.7 pre-osteoclasts, we demonstrated that overexpression of ZAS3 promoted osteoclastogenesis and the expression of crucial osteoclastic molecules, including phospho-p38, c-Jun, NFATc1, TRAP and CTSK. Contrarily, ZAS3 silencing by siRNA inhibited osteoclastogenesis. Co-immunoprecipitation experiments demonstrated that ZAS3 associated with TRAF6, the major receptor associated molecule in RANK signaling. Furthermore, EMSA suggested that nuclear ZAS3 could regulate transcription by binding to gene regulatory elements. CONCLUSION/SIGNIFICANCE: Collectively, the data suggested a novel role of ZAS3 as a positive regulator of osteoclast differentiation. ZAS3 deficiency caused increased bone mass, at least in part due to decreased osteoclast formation and bone resorption. These functions of ZAS3 were mediated via activation of multiple intracellular targets. In the cytoplasmic compartment, ZAS3 associated with TRAF6 to control NF-kB and MAP kinase signaling cascades. Nuclear ZAS3 acted as a transcriptional regulator for osteoclast-associated genes. Additionally, ZAS3 activated NFATc1 required for the integration of RANK signaling in the terminal differentiation of osteoclasts. Thus, ZAS3 was a crucial molecule in osteoclast differentiation, which might potentially serve as a target in the design of therapeutic interventions for the treatment of bone diseases related to increased osteoclast activity such as postmenopausal osteoporosis, Paget's disease, and rheumatoid arthritis.
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spelling pubmed-30484312011-03-09 The Large Zinc Finger Protein ZAS3 Is a Critical Modulator of Osteoclastogenesis Liu, Shujun Madiai, Francesca Hackshaw, Kevin V. Allen, Carl E. Carl, Joseph Huschart, Emily Karanfilov, Chris Litsky, Alan Hickey, Christopher J. Marcucci, Guido Huja, Sarandeep Agarwal, Sudha Yu, Jianhua Caligiuri, Michael A. Wu, Lai-Chu PLoS One Research Article BACKGROUND: Mice deficient in the large zinc finger protein, ZAS3, show postnatal increase in bone mass suggesting that ZAS3 is critical in the regulation of bone homeostasis. Although ZAS3 has been shown to inhibit osteoblast differentiation, its role on osteoclastogenesis has not been determined. In this report we demonstrated the role of ZAS3 in bone resorption by examining the signaling mechanisms involved in osteoclastogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Comparison of adult wild-type and ZAS3 knockout (ZAS3−/−) mice showed that ZAS3 deficiency led to thicker bones that are more resistant to mechanical fracture. Additionally, ZAS3−/− bones showed fewer osteoclasts and inefficient M-CSF/sRANKL-mediated osteoclastogenesis ex vivo. Utilizing RAW 264.7 pre-osteoclasts, we demonstrated that overexpression of ZAS3 promoted osteoclastogenesis and the expression of crucial osteoclastic molecules, including phospho-p38, c-Jun, NFATc1, TRAP and CTSK. Contrarily, ZAS3 silencing by siRNA inhibited osteoclastogenesis. Co-immunoprecipitation experiments demonstrated that ZAS3 associated with TRAF6, the major receptor associated molecule in RANK signaling. Furthermore, EMSA suggested that nuclear ZAS3 could regulate transcription by binding to gene regulatory elements. CONCLUSION/SIGNIFICANCE: Collectively, the data suggested a novel role of ZAS3 as a positive regulator of osteoclast differentiation. ZAS3 deficiency caused increased bone mass, at least in part due to decreased osteoclast formation and bone resorption. These functions of ZAS3 were mediated via activation of multiple intracellular targets. In the cytoplasmic compartment, ZAS3 associated with TRAF6 to control NF-kB and MAP kinase signaling cascades. Nuclear ZAS3 acted as a transcriptional regulator for osteoclast-associated genes. Additionally, ZAS3 activated NFATc1 required for the integration of RANK signaling in the terminal differentiation of osteoclasts. Thus, ZAS3 was a crucial molecule in osteoclast differentiation, which might potentially serve as a target in the design of therapeutic interventions for the treatment of bone diseases related to increased osteoclast activity such as postmenopausal osteoporosis, Paget's disease, and rheumatoid arthritis. Public Library of Science 2011-03-03 /pmc/articles/PMC3048431/ /pubmed/21390242 http://dx.doi.org/10.1371/journal.pone.0017161 Text en Liu et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Liu, Shujun
Madiai, Francesca
Hackshaw, Kevin V.
Allen, Carl E.
Carl, Joseph
Huschart, Emily
Karanfilov, Chris
Litsky, Alan
Hickey, Christopher J.
Marcucci, Guido
Huja, Sarandeep
Agarwal, Sudha
Yu, Jianhua
Caligiuri, Michael A.
Wu, Lai-Chu
The Large Zinc Finger Protein ZAS3 Is a Critical Modulator of Osteoclastogenesis
title The Large Zinc Finger Protein ZAS3 Is a Critical Modulator of Osteoclastogenesis
title_full The Large Zinc Finger Protein ZAS3 Is a Critical Modulator of Osteoclastogenesis
title_fullStr The Large Zinc Finger Protein ZAS3 Is a Critical Modulator of Osteoclastogenesis
title_full_unstemmed The Large Zinc Finger Protein ZAS3 Is a Critical Modulator of Osteoclastogenesis
title_short The Large Zinc Finger Protein ZAS3 Is a Critical Modulator of Osteoclastogenesis
title_sort large zinc finger protein zas3 is a critical modulator of osteoclastogenesis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048431/
https://www.ncbi.nlm.nih.gov/pubmed/21390242
http://dx.doi.org/10.1371/journal.pone.0017161
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