title: CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts.
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.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115 Department of Medicine and Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Greenblatt
authors.affiliation: Department of Medicine and Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065 Department of Microbiology, Brain Korea 21 PLUS Project for Medical Sciences and Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea Department of Microbiology, Brain Korea 21 PLUS Project for Medical Sciences and Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Kwang Hwan
authors.initials: KH
authors.lastname: Park
authors.affiliation: Department of Medicine and Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Hwanhee
authors.initials: H
authors.lastname: Oh
authors.affiliation: Department of Medicine and Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Jung-Min
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Medicine and Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Dong Yeon
authors.initials: DY
authors.lastname: Shin
authors.affiliation: Department of Microbiology, Brain Korea 21 PLUS Project for Medical Sciences and Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Jae Myun
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Brain Korea 21 PLUS Project for Medical Sciences and Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Lee
authors.affiliation: National Center for Advancing Translational Sciences/National Institutes of Health, Rockville, MD 20850.
authors.forename: Anju
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Republic of Korea.
authors.forename: Ki-young
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Hu
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Changchun
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Department of Medicine, Division of Rheumatology, Allergy, and Immunology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors.forename: Julia F
authors.initials: JF
authors.lastname: Charles
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.affiliation: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115 Department of Physiology and STAR on Craniofacial and Skeletal Disorders, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Sutada
authors.initials: S
authors.lastname: Lotinun
authors.affiliation: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115.
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
authors.affiliation: Department of Microbiology and Immunology, Columbia University, College of Physicians and Surgeons, New York, NY 10032.
authors.forename: Sankar
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Medicine and Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065 jas2060@med.cornell.edu.
authors.forename: Jae-Hyuck
authors.initials: JH
authors.lastname: Shim
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001846:Bone Development / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008156:Luciferases; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology; D010010:Osteoclasts / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000502:physiology*; D054875:Ubiquitination; D000074405:Valosin Containing Protein
chemical_list: C499838:CHMP5 protein, human; D018797:Cell Cycle Proteins; D017931:DNA Primers; D056827:Endosomal Sorting Complexes Required for Transport; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D000072000:NF-KappaB Inhibitor alpha; D008156:Luciferases; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse