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Blocking of the Ubiquitin-Proteasome System Prevents Inflammation-Induced Bone Loss by Accelerating M-CSF Receptor c-Fms Degradation in Osteoclast Differentiation.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2017 Sep 25; Vol. 18 (10). Date of Electronic Publication: 2017 Sep 25. - Publication Year :
- 2017
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Abstract
- Anti-osteoporotic activity of a blocker of the ubiquitin-proteasome system, bortezomib, has known to be achieved by directly opposed action in increased bone formation by osteoblasts and in decreased bone destruction by osteoclasts. However, the mechanisms underlying the proteasome blocker inhibition of osteoclast differentiation and function are not fully understood. Here, we observed that proteasome inhibitors, such as MG132 and bortezomib, in osteoclasts accelerated the degradation of c-Fms, a cognate receptor of macrophage colony-stimulating factor (M-CSF), and did not affect the amount of receptor activator of nuclear factor kappa-B (RANK), a receptor of receptor activator of nuclear factor kappa-B ligand (RANKL). c-Fms degradation induced by proteasome inhibitors was controlled by the activation of p38/tumor necrosis factor-alpha converting enzyme (TACE)-mediated regulated intramembrane proteolysis (RIPping). This was validated through the restoration of c-Fms using specific inhibitors of p38 and TACE, and a stimulation of p38-dependent TACE. In addition, c-Fms degradation by proteasome inhibition completely blocked M-CSF-mediated intrinsic signalling and led to the suppression of osteoclast differentiation and bone resorption. In a mouse model with intraperitoneal administration of lipopolysaccharide (LPS) that stimulates osteoclast formation and leads to bone loss, proteasome blockers prevented LPS-induced inflammatory bone resorption due to a decrease in the number of c-Fms-positive osteoclasts. Our study showed that accelerating c-Fms proteolysis by proteasome inhibitors may be a therapeutic option for inflammation-induced bone loss.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Apoptosis drug effects
Bone Resorption pathology
Bone Resorption prevention & control
Bortezomib pharmacology
Cell Differentiation drug effects
Cell Differentiation genetics
Cell Proliferation drug effects
Disease Models, Animal
Humans
Macrophage Colony-Stimulating Factor metabolism
Male
Mice
Proteasome Inhibitors pharmacology
Proteolysis
Receptor, Macrophage Colony-Stimulating Factor genetics
Bone Resorption etiology
Bone Resorption metabolism
Inflammation complications
Osteoclasts cytology
Osteoclasts metabolism
Proteasome Endopeptidase Complex metabolism
Receptor, Macrophage Colony-Stimulating Factor metabolism
Ubiquitin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 18
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 28946669
- Full Text :
- https://doi.org/10.3390/ijms18102054