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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 
 JOURNAL OF EXPERIMENTAL MEDICINE, Vol.212(8) : 1283-1301, 2015 
Journal Title
Issue Date
Adenosine Triphosphatases/metabolism ; Animals ; Base Sequence ; Bone Development/genetics ; Bone Development/physiology* ; Cell Cycle Proteins/metabolism ; Cell Differentiation/physiology ; DNA Primers/genetics ; Endosomal Sorting Complexes Required for Transport/metabolism* ; Fluorescent Antibody Technique ; HEK293 Cells ; Humans ; I-kappa B Proteins/metabolism ; Immunoblotting ; Immunohistochemistry ; In Situ Hybridization ; Luciferases ; Mice ; Mice, Transgenic ; Molecular Sequence Data ; NF-KappaB Inhibitor alpha ; NF-kappa B/metabolism* ; Osteoblasts/cytology ; Osteoclasts/metabolism* ; RANK Ligand/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Sequence Analysis, RNA ; Signal Transduction/physiology* ; Ubiquitination ; Valosin Containing Protein
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.
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1. College of Medicine (의과대학) > Dept. of Orthopedic Surgery (정형외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Park, Kwang Hwan(박광환) ORCID logo https://orcid.org/0000-0002-2110-0559
Lee, Jae Myun(이재면) ORCID logo https://orcid.org/0000-0002-5273-3113
Lee, Jin Woo(이진우) ORCID logo https://orcid.org/0000-0002-0293-9017
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