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

TitleCHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts.
Publication TypeJournal Article
Year of Publication2015
AuthorsGreenblatt MB, Park KHwan, Oh H, Kim J-M, Shin DYeon, Lee JMyun, Lee JWoo, Singh A, Lee K-Y, Hu D, Xiao C, Charles JF, Penninger JM, Lotinun S, Baron R, Ghosh S, Shim J-H
JournalJ Exp Med
Volume212
Issue8
Pagination1283-301
Date Published2015 Jul 27
ISSN1540-9538
KeywordsAdenosine Triphosphatases, Animals, Base Sequence, Bone Development, Cell Cycle Proteins, Cell Differentiation, DNA Primers, Endosomal Sorting Complexes Required for Transport, Fluorescent Antibody Technique, HEK293 Cells, Humans, I-kappa B Proteins, Immunoblotting, Immunohistochemistry, In Situ Hybridization, Luciferases, Mice, Mice, Transgenic, Molecular Sequence Data, NF-kappa B, NF-KappaB Inhibitor alpha, Osteoblasts, Osteoclasts, RANK Ligand, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, RNA, Signal Transduction, Ubiquitination, Valosin Containing Protein
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.

DOI10.1084/jem.20150407
Alternate JournalJ Exp Med
PubMed ID26195726
PubMed Central IDPMC4516796
Grant ListK08 AR062590 / AR / NIAMS NIH HHS / United States
1 R01 AR068983-01 / AR / NIAMS NIH HHS / United States
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Matthew B. Greenblatt, M.D., Ph.D.

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