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Creation of RANKL mutants with low affinity for decoy receptor OPG and their potential anti‐fibrosis activity
Fibrosis is characterized by the progressive alteration of the tissue structure due to the excessive production of extracellular matrix (ECM). The signaling system encompassing Receptor Activator of Nuclear factor NF‐κB Ligand (RANKL)/RANK/Osteoprotegerin (OPG) was discovered to play an important ro...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852375/ https://www.ncbi.nlm.nih.gov/pubmed/31081236 http://dx.doi.org/10.1111/febs.14925 |
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author | Wang, Yizhou Michiels, Timo Setroikromo, Rita van Merkerk, Ronald Cool, Robbert H. Quax, Wim J. |
author_facet | Wang, Yizhou Michiels, Timo Setroikromo, Rita van Merkerk, Ronald Cool, Robbert H. Quax, Wim J. |
author_sort | Wang, Yizhou |
collection | PubMed |
description | Fibrosis is characterized by the progressive alteration of the tissue structure due to the excessive production of extracellular matrix (ECM). The signaling system encompassing Receptor Activator of Nuclear factor NF‐κB Ligand (RANKL)/RANK/Osteoprotegerin (OPG) was discovered to play an important role in the regulation of ECM formation and degradation in bone tissue. However, whether and how this signaling pathway plays a role in liver or pulmonary ECM degradation is unclear up to now. Interestingly, increased decoy receptor OPG levels are found in fibrotic tissues. We hypothesize that RANKL can stimulate RANK on macrophages and initiate the process of ECM degradation. This process may be inhibited by highly expressed OPG in fibrotic conditions. In this case, RANKL mutants that can bind to RANK without binding to OPG might become promising therapeutic candidates. In this study, we built a structure‐based library containing 44 RANKL mutants and found that the Q236 residue of RANKL is important for OPG binding. We show that RANKL_Q236D can activate RAW cells to initiate the process of ECM degradation and is able to escape from the obstruction by exogenous OPG. We propose that the generation of RANKL mutants with reduced affinity for OPG is a promising strategy for the exploration of new therapeutics against fibrosis. |
format | Online Article Text |
id | pubmed-6852375 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-68523752019-11-20 Creation of RANKL mutants with low affinity for decoy receptor OPG and their potential anti‐fibrosis activity Wang, Yizhou Michiels, Timo Setroikromo, Rita van Merkerk, Ronald Cool, Robbert H. Quax, Wim J. FEBS J Original Articles Fibrosis is characterized by the progressive alteration of the tissue structure due to the excessive production of extracellular matrix (ECM). The signaling system encompassing Receptor Activator of Nuclear factor NF‐κB Ligand (RANKL)/RANK/Osteoprotegerin (OPG) was discovered to play an important role in the regulation of ECM formation and degradation in bone tissue. However, whether and how this signaling pathway plays a role in liver or pulmonary ECM degradation is unclear up to now. Interestingly, increased decoy receptor OPG levels are found in fibrotic tissues. We hypothesize that RANKL can stimulate RANK on macrophages and initiate the process of ECM degradation. This process may be inhibited by highly expressed OPG in fibrotic conditions. In this case, RANKL mutants that can bind to RANK without binding to OPG might become promising therapeutic candidates. In this study, we built a structure‐based library containing 44 RANKL mutants and found that the Q236 residue of RANKL is important for OPG binding. We show that RANKL_Q236D can activate RAW cells to initiate the process of ECM degradation and is able to escape from the obstruction by exogenous OPG. We propose that the generation of RANKL mutants with reduced affinity for OPG is a promising strategy for the exploration of new therapeutics against fibrosis. John Wiley and Sons Inc. 2019-05-25 2019-09 /pmc/articles/PMC6852375/ /pubmed/31081236 http://dx.doi.org/10.1111/febs.14925 Text en © 2019 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Wang, Yizhou Michiels, Timo Setroikromo, Rita van Merkerk, Ronald Cool, Robbert H. Quax, Wim J. Creation of RANKL mutants with low affinity for decoy receptor OPG and their potential anti‐fibrosis activity |
title | Creation of RANKL mutants with low affinity for decoy receptor OPG and their potential anti‐fibrosis activity |
title_full | Creation of RANKL mutants with low affinity for decoy receptor OPG and their potential anti‐fibrosis activity |
title_fullStr | Creation of RANKL mutants with low affinity for decoy receptor OPG and their potential anti‐fibrosis activity |
title_full_unstemmed | Creation of RANKL mutants with low affinity for decoy receptor OPG and their potential anti‐fibrosis activity |
title_short | Creation of RANKL mutants with low affinity for decoy receptor OPG and their potential anti‐fibrosis activity |
title_sort | creation of rankl mutants with low affinity for decoy receptor opg and their potential anti‐fibrosis activity |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852375/ https://www.ncbi.nlm.nih.gov/pubmed/31081236 http://dx.doi.org/10.1111/febs.14925 |
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