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

Authors
 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 
Citation
 Journal of Experimental Medicine, Vol.212(8) : 1283-1301, 2015 
Journal Title
 Journal of Experimental Medicine 
ISSN
 0022-1007 
Issue Date
2015
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.
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/140833
DOI
10.1084/jem.20150407
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Orthopedic Surgery (정형외과학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실)
Yonsei Authors
박광환(Park, Kwang Hwan) ; 이재면(Lee, Jae Myun) ; 이진우(Lee, Jin Woo)
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Full Text
http://jem.rupress.org/content/212/8/1283
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