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Vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained RANKL signaling
Receptor activator of NF-κB (RANK) plays a critical role in osteoclastogenesis, an essential process for the initiation of bone remodeling to maintain healthy bone mass and structure. Although the signaling and function of RANK have been investigated extensively, much less is known about the negativ...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601351/ https://www.ncbi.nlm.nih.gov/pubmed/23509071 http://dx.doi.org/10.1083/jcb.201207154 |
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author | Xia, Wen-Fang Tang, Fu-Lei Xiong, Lei Xiong, Shan Jung, Ji-Ung Lee, Dae-Hoon Li, Xing-Sheng Feng, Xu Mei, Lin Xiong, Wen-Cheng |
author_facet | Xia, Wen-Fang Tang, Fu-Lei Xiong, Lei Xiong, Shan Jung, Ji-Ung Lee, Dae-Hoon Li, Xing-Sheng Feng, Xu Mei, Lin Xiong, Wen-Cheng |
author_sort | Xia, Wen-Fang |
collection | PubMed |
description | Receptor activator of NF-κB (RANK) plays a critical role in osteoclastogenesis, an essential process for the initiation of bone remodeling to maintain healthy bone mass and structure. Although the signaling and function of RANK have been investigated extensively, much less is known about the negative regulatory mechanisms of its signaling. We demonstrate in this paper that RANK trafficking, signaling, and function are regulated by VPS35, a major component of the retromer essential for selective endosome to Golgi retrieval of membrane proteins. VPS35 loss of function altered RANK ligand (RANKL)–induced RANK distribution, enhanced RANKL sensitivity, sustained RANKL signaling, and increased hyperresorptive osteoclast (OC) formation. Hemizygous deletion of the Vps35 gene in mice promoted hyperresorptive osteoclastogenesis, decreased bone formation, and caused a subsequent osteoporotic deficit, including decreased trabecular bone volumes and reduced trabecular thickness and density in long bones. These results indicate that VPS35 critically deregulates RANK signaling, thus restraining increased formation of hyperresorptive OCs and preventing osteoporotic deficits. |
format | Online Article Text |
id | pubmed-3601351 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-36013512013-09-18 Vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained RANKL signaling Xia, Wen-Fang Tang, Fu-Lei Xiong, Lei Xiong, Shan Jung, Ji-Ung Lee, Dae-Hoon Li, Xing-Sheng Feng, Xu Mei, Lin Xiong, Wen-Cheng J Cell Biol Research Articles Receptor activator of NF-κB (RANK) plays a critical role in osteoclastogenesis, an essential process for the initiation of bone remodeling to maintain healthy bone mass and structure. Although the signaling and function of RANK have been investigated extensively, much less is known about the negative regulatory mechanisms of its signaling. We demonstrate in this paper that RANK trafficking, signaling, and function are regulated by VPS35, a major component of the retromer essential for selective endosome to Golgi retrieval of membrane proteins. VPS35 loss of function altered RANK ligand (RANKL)–induced RANK distribution, enhanced RANKL sensitivity, sustained RANKL signaling, and increased hyperresorptive osteoclast (OC) formation. Hemizygous deletion of the Vps35 gene in mice promoted hyperresorptive osteoclastogenesis, decreased bone formation, and caused a subsequent osteoporotic deficit, including decreased trabecular bone volumes and reduced trabecular thickness and density in long bones. These results indicate that VPS35 critically deregulates RANK signaling, thus restraining increased formation of hyperresorptive OCs and preventing osteoporotic deficits. The Rockefeller University Press 2013-03-18 /pmc/articles/PMC3601351/ /pubmed/23509071 http://dx.doi.org/10.1083/jcb.201207154 Text en © 2013 Xia 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 | Research Articles Xia, Wen-Fang Tang, Fu-Lei Xiong, Lei Xiong, Shan Jung, Ji-Ung Lee, Dae-Hoon Li, Xing-Sheng Feng, Xu Mei, Lin Xiong, Wen-Cheng Vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained RANKL signaling |
title | Vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained RANKL signaling |
title_full | Vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained RANKL signaling |
title_fullStr | Vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained RANKL signaling |
title_full_unstemmed | Vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained RANKL signaling |
title_short | Vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained RANKL signaling |
title_sort | vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained rankl signaling |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601351/ https://www.ncbi.nlm.nih.gov/pubmed/23509071 http://dx.doi.org/10.1083/jcb.201207154 |
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