CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts

Matthew B. Greenblatt, Kwang Hwan Park, Hwanhee Oh, Jung Min Kim, Dong Yeon Shin, Jae Myun Lee, Jin Woo Lee, Anju Singh, Ki Young Lee, Dorothy Hu, Changchun Xiao, Julia F. Charles, Josef M. Penninger, Sutada Lotinun, Roland Baron, Sankar Ghosh, Jae Hyuck Shim

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

Abstract

Physiological bone remodeling requires that bone formation by osteoblasts be tightly coupled to bone resorption by osteoclasts. However, relatively little is understood about how this coupling is regulated. Here, we demonstrate that modulation of NF-κB signaling in osteoclasts via a novel activity of charged multivesicular body protein 5 (CHMP5) is a key determinant of systemic rates of bone turnover. A conditional deletion of CHMP5 in osteoclasts leads to increased bone resorption by osteoclasts coupled with exuberant bone formation by osteoblasts, resembling an early onset, polyostotic form of human Paget's disease of bone (PDB). These phenotypes are reversed by haploinsufficiency for Rank, as well as by antiresorptive treatments, including alendronate, zolendronate, and OPG-Fc. Accordingly, CHMP5-deficient osteoclasts display increased RANKL-induced NF-κB activation and osteoclast differentiation. Biochemical analysis demonstrated that CHMP5 cooperates with the PDB genetic risk factor valosin-containing protein (VCP/p97) to stabilize the inhibitor of NF-κBα (IκBα), down-regulating ubiquitination of IκBα via the deubiquitinating enzyme USP15. Thus, CHMP5 tunes NF-κB signaling downstream of RANK in osteoclasts to dampen osteoclast differentiation, osteoblast coupling and bone turnover rates, and disruption of CHMP5 activity results in a PDB-like skeletal disorder.

Original languageEnglish
Pages (from-to)1283-1301
Number of pages19
JournalJournal of Experimental Medicine
Volume212
Issue number8
DOIs
Publication statusPublished - 2015 Jul 27

Bibliographical note

Funding Information:
This work was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health (J.-H. Shim; 1 R01 AR068983-01). J.M. Penninger was supported by an Advanced European Research Council grant and an Innovator Award from the Era of Hope/Department of Defense. The authors declare no competing financial interests.

Funding Information:
This work was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health (J.-H. Shim; 1 R01 AR068983-01). J.M. Penninger was supported by an Advanced European Research Council grant and an Innovator Award from the Era of Hope/Department of Defense.

Publisher Copyright:
© 2015 Greenblatt 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/).

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Fingerprint

Dive into the research topics of 'CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts'. Together they form a unique fingerprint.

Cite this