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, jinwoo 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

Research output: Contribution to journalArticle

20 Citations (Scopus)

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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Multivesicular Bodies
Bone Remodeling
Osteoclasts
Osteitis Deformans
Proteins
Osteoblasts
Bone Resorption
Osteogenesis
Haploinsufficiency
Alendronate
Ubiquitination
Phenotype

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., ... 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
Greenblatt, Matthew B. ; Park, Kwang H.wan ; Oh, Hwanhee ; Kim, Jung Min ; Shin, Dong Y.eon ; Lee, Jae M.yun ; lee, jinwoo ; Singh, Anju ; Lee, Ki young ; Hu, Dorothy ; Xiao, Changchun ; Charles, Julia F. ; Penninger, Josef M. ; Lotinun, Sutada ; Baron, Roland ; Ghosh, Sankar ; Shim, Jae Hyuck. / CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts. In: The Journal of experimental medicine. 2015 ; Vol. 212, No. 8. pp. 1283-1301.
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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.",
author = "Greenblatt, {Matthew B.} and Park, {Kwang H.wan} and Hwanhee Oh and Kim, {Jung Min} and Shin, {Dong Y.eon} and Lee, {Jae M.yun} and jinwoo lee and Anju Singh and Lee, {Ki young} and Dorothy Hu and Changchun Xiao and Charles, {Julia F.} and Penninger, {Josef M.} and Sutada Lotinun and Roland Baron and Sankar Ghosh and Shim, {Jae Hyuck}",
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Greenblatt, MB, Park, KHW, Oh, H, Kim, JM, Shin, DYE, Lee, JMY, lee, J, Singh, A, Lee, KY, Hu, D, Xiao, C, Charles, JF, Penninger, JM, Lotinun, S, Baron, R, Ghosh, S & Shim, JH 2015, 'CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts', The Journal of experimental medicine, vol. 212, no. 8, pp. 1283-1301. https://doi.org/10.1084/jem.20150407

CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts. / Greenblatt, Matthew B.; Park, Kwang H.wan; Oh, Hwanhee; Kim, Jung Min; Shin, Dong Y.eon; Lee, Jae M.yun; lee, jinwoo; Singh, Anju; Lee, Ki young; Hu, Dorothy; Xiao, Changchun; Charles, Julia F.; Penninger, Josef M.; Lotinun, Sutada; Baron, Roland; Ghosh, Sankar; Shim, Jae Hyuck.

In: The Journal of experimental medicine, Vol. 212, No. 8, 27.07.2015, p. 1283-1301.

Research output: Contribution to journalArticle

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T1 - CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts

AU - Greenblatt, Matthew B.

AU - Park, Kwang H.wan

AU - Oh, Hwanhee

AU - Kim, Jung Min

AU - Shin, Dong Y.eon

AU - Lee, Jae M.yun

AU - lee, jinwoo

AU - Singh, Anju

AU - Lee, Ki young

AU - Hu, Dorothy

AU - Xiao, Changchun

AU - Charles, Julia F.

AU - Penninger, Josef M.

AU - Lotinun, Sutada

AU - Baron, Roland

AU - Ghosh, Sankar

AU - Shim, Jae Hyuck

PY - 2015/7/27

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N2 - 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.

AB - 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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