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The role of CHMP5 as a regulator of NF-κB signaling in Paget’s disease of bone-like disorder
DC Field | Value | Language |
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dc.contributor.author | 박광환 | - |
dc.date.accessioned | 2017-02-23T11:16:10Z | - |
dc.date.available | 2017-02-23T11:16:10Z | - |
dc.date.issued | 2015 | - |
dc.identifier.uri | https://ir.ymlib.yonsei.ac.kr/handle/22282913/146088 | - |
dc.description | Dept. of Medical Science/박사 | - |
dc.description.abstract | Spatiotemporal coupling of the activity of osteoblasts and osteoclasts is required for balance in bone homeostasis, and dysregulation of this process is a major mechanism in the pathogenesis of Paget’s disease of bone (PDB). PDB is a prevalent metabolic disorder characterized by exuberant bone turnover with increased osteoclastic bone resorption followed by an increase in osteoblastic bone formation. Despite major advances in understanding the pathophysiology of PDB, the mechanistic contributions of genetic components to PDB development remain unclear. Here I demonstrated that the loss of charged multivesicular body protein 5 (Chmp5) in osteoclasts, lead to PDB-like disorder in mice, which manifested as the progressive deposition of pagetoid bone lesions and increased bone turnover. The phenotypes in Chmp5 knock-out micewere alleviated by antiresorptive treatments such as bisphosphonates and a RANKL (Receptor activator of nuclear factor kappa-B ligand) inhibitor. Accordingly, Chmp5 deletion enhances NF-κB (Nuclear factor Kappa B) activation and osteoclast differentiation in response to RANKL, in which mechanism it stabilizes the inhibitor of NF-κB (IκB) by inhibiting ubiquitin-mediated proteasomal degradation via the interaction with the deubiquitinating enzyme USP15. Chmp5-deficient osteoclasts also increased osteoblast activity in the culture along with elevated levels of clastokines and Ephrin B reverse signaling. These findings reveal Chmp5 as an essential molecule in the osteoclast regulation of new bone formation and bone remodeling and provide a new mouse model of PDB-like disorder. Furthermore, this mouse model will be an ideal in vivo tool to identify therapeutic targets for the skeletal disorders with dysregulated bone remodeling, including osteoporosis and PDB. | - |
dc.description.statementOfResponsibility | restriction | - |
dc.format | application/pdf | - |
dc.publisher | Graduate School, Yonsei University | - |
dc.rights | CC BY-NC-ND 2.0 KR | - |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/2.0/kr/ | - |
dc.title | The role of CHMP5 as a regulator of NF-κB signaling in Paget’s disease of bone-like disorder | - |
dc.title.alternative | 골파제트양 질환에서 NF-κB 신호전달 조절자로서의 CHMP5 의 역할 | - |
dc.type | Thesis | - |
dc.contributor.department | Dept. of Orthopedic Surgery (정형외과학교실) | - |
dc.contributor.localId | A01437 | - |
dc.identifier.url | https://ymlib.yonsei.ac.kr/catalog/search/book-detail/?cid=CAT000000216235 | - |
dc.contributor.alternativeName | Park, Kwang Hwan | - |
dc.contributor.affiliatedAuthor | 박광환 | - |
dc.type.local | Dissertation | - |
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