Optineurin Negatively Regulates Osteoclast Differentiation by Modulating NF-κB and Interferon Signaling: Implications for Paget’s Disease
Paget’s disease of bone (PDB) is a common disease characterized by osteoclast activation that leads to various skeletal complications. Susceptibility to PDB is mediated by a common variant at the optineurin (OPTN) locus, which is associated with reduced levels of mRNA. However, it is unclear how thi...
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| Format: | Online |
| Language: | English |
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Cell Press
2015
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646838/ |
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pubmed-4646838 |
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pubmed-46468382015-12-08 Optineurin Negatively Regulates Osteoclast Differentiation by Modulating NF-κB and Interferon Signaling: Implications for Paget’s Disease Obaid, Rami Wani, Sachin E. Azfer, Asim Hurd, Toby Jones, Ruth Cohen, Philip Ralston, Stuart H. Albagha, Omar M.E. Report Paget’s disease of bone (PDB) is a common disease characterized by osteoclast activation that leads to various skeletal complications. Susceptibility to PDB is mediated by a common variant at the optineurin (OPTN) locus, which is associated with reduced levels of mRNA. However, it is unclear how this leads to the development of PDB. Here, we show that OPTN acts as a negative regulator of osteoclast differentiation in vitro and that mice with a loss-of-function mutation in Optn have increased osteoclast activity and bone turnover. Osteoclasts derived from Optn mutant mice have an increase in NF-κB activation and a reduction in interferon beta expression in response to RANKL when compared to wild-type mice. These studies identify OPTN as a regulator of bone resorption and are consistent with a model whereby genetically determined reductions in OPTN expression predispose to PDB by enhancing osteoclast differentiation. Cell Press 2015-10-29 /pmc/articles/PMC4646838/ /pubmed/26527009 http://dx.doi.org/10.1016/j.celrep.2015.09.071 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Obaid, Rami Wani, Sachin E. Azfer, Asim Hurd, Toby Jones, Ruth Cohen, Philip Ralston, Stuart H. Albagha, Omar M.E. |
| spellingShingle |
Obaid, Rami Wani, Sachin E. Azfer, Asim Hurd, Toby Jones, Ruth Cohen, Philip Ralston, Stuart H. Albagha, Omar M.E. Optineurin Negatively Regulates Osteoclast Differentiation by Modulating NF-κB and Interferon Signaling: Implications for Paget’s Disease |
| author_facet |
Obaid, Rami Wani, Sachin E. Azfer, Asim Hurd, Toby Jones, Ruth Cohen, Philip Ralston, Stuart H. Albagha, Omar M.E. |
| author_sort |
Obaid, Rami |
| title |
Optineurin Negatively Regulates Osteoclast Differentiation by Modulating NF-κB and Interferon Signaling: Implications for Paget’s Disease |
| title_short |
Optineurin Negatively Regulates Osteoclast Differentiation by Modulating NF-κB and Interferon Signaling: Implications for Paget’s Disease |
| title_full |
Optineurin Negatively Regulates Osteoclast Differentiation by Modulating NF-κB and Interferon Signaling: Implications for Paget’s Disease |
| title_fullStr |
Optineurin Negatively Regulates Osteoclast Differentiation by Modulating NF-κB and Interferon Signaling: Implications for Paget’s Disease |
| title_full_unstemmed |
Optineurin Negatively Regulates Osteoclast Differentiation by Modulating NF-κB and Interferon Signaling: Implications for Paget’s Disease |
| title_sort |
optineurin negatively regulates osteoclast differentiation by modulating nf-κb and interferon signaling: implications for paget’s disease |
| description |
Paget’s disease of bone (PDB) is a common disease characterized by osteoclast activation that leads to various skeletal complications. Susceptibility to PDB is mediated by a common variant at the optineurin (OPTN) locus, which is associated with reduced levels of mRNA. However, it is unclear how this leads to the development of PDB. Here, we show that OPTN acts as a negative regulator of osteoclast differentiation in vitro and that mice with a loss-of-function mutation in Optn have increased osteoclast activity and bone turnover. Osteoclasts derived from Optn mutant mice have an increase in NF-κB activation and a reduction in interferon beta expression in response to RANKL when compared to wild-type mice. These studies identify OPTN as a regulator of bone resorption and are consistent with a model whereby genetically determined reductions in OPTN expression predispose to PDB by enhancing osteoclast differentiation. |
| publisher |
Cell Press |
| publishDate |
2015 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646838/ |
| _version_ |
1613501865902735360 |