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CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts
Matthew B Greenblatt1, Kwang Hwan Park2, Hwanhee Oh3
1Department 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.
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.
Insights
Charged multivesicular body protein 5 (CHMP5) regulates bone turnover by modulating NF-κB signaling in osteoclasts. Disruption of CHMP5 causes Paget's disease-like bone disorders.
Area of Science:
- Cell Biology
- Bone Biology
- Molecular Biology
Background:
- Bone remodeling involves coupled osteoblast and osteoclast activity, but regulatory mechanisms remain unclear.
- Osteoclast-mediated bone resorption and osteoblast-mediated bone formation must be tightly regulated for skeletal homeostasis.
Purpose of the Study:
- To investigate the role of charged multivesicular body protein 5 (CHMP5) in regulating NF-κB signaling within osteoclasts.
- To determine the impact of CHMP5 modulation on bone turnover rates and skeletal disease.
Main Methods:
- Conditional deletion of CHMP5 in osteoclasts.
- Analysis of bone resorption and formation markers.
- Assessment of NF-κB signaling pathway activation.
- Biochemical analysis of protein interactions (CHMP5, VCP/p97, IκBα, USP15).
Main Results:
- CHMP5 deletion in osteoclasts increased bone resorption and osteoblast activity, mimicking Paget's disease of bone (PDB).
- Phenotypes were reversed by Rank haploinsufficiency and antiresorptive drugs (alendronate, zolendronate, OPG-Fc).
- CHMP5 deficiency enhanced RANKL-induced NF-κB activation and osteoclast differentiation, involving stabilization of IκBα via USP15 and VCP/p97.
Conclusions:
- CHMP5 acts as a crucial regulator of NF-κB signaling downstream of RANK in osteoclasts.
- CHMP5 dampens osteoclast differentiation, osteoblast coupling, and overall bone turnover.
- Disruption of CHMP5 function leads to a PDB-like skeletal disorder, highlighting its therapeutic potential.
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