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

Matthew B. Greenblatt, Kwang H.wan Park, Hwanhee Oh, Jung Min Kim, Dong Y.eon Shin, Jae M.yun Lee, Jin W.oo 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

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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.

Original languageEnglish
Pages (from-to)1283-1301
Number of pages19
JournalThe Journal of experimental medicine
Volume212
Issue number8
DOIs
Publication statusPublished - 2015 Jul 27

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Greenblatt, M. B., Park, K. H. W., Oh, H., Kim, J. M., Shin, D. Y. E., Lee, J. M. Y., Lee, J. W. O., Singh, A., Lee, K. Y., Hu, D., Xiao, C., Charles, J. F., Penninger, J. M., Lotinun, S., Baron, R., Ghosh, S., & Shim, J. H. (2015). CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts. The Journal of experimental medicine, 212(8), 1283-1301. https://doi.org/10.1084/jem.20150407