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

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 o...

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Bibliographic Details
Published in:The Journal of experimental medicine 2015-07, Vol.212 (8), p.1283-1301
Main Authors: Greenblatt, Matthew B, Park, Kwang Hwan, Oh, Hwanhee, Kim, Jung-Min, Shin, Dong Yeon, Lee, Jae Myun, Lee, Jin Woo, Singh, Anju, Lee, Ki-young, Hu, Dorothy, Xiao, Changchun, Charles, Julia F, Penninger, Josef M, Lotinun, Sutada, Baron, Roland, Ghosh, Sankar, Shim, Jae-Hyuck
Format: Article
Language:English
Subjects:
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-kappa B - metabolism
NF-KappaB Inhibitor alpha
Osteoblasts - cytology
Osteoclasts - metabolism
RANK Ligand - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Sequence Analysis, RNA
Signal Transduction - physiology
Ubiquitination
Valosin Containing Protein
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Summary: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.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20150407