Cargando…
Effects of interleukin‐17A in nucleus pulposus cells and its small‐molecule inhibitors for intervertebral disc disease
Intervertebral discs (IVD) degeneration, which is caused by ageing or mechanical stress, leads to IVD disease, including back pain and sciatica. The cytokine interleukin (IL)‐17A is elevated in NP cells during IVD disease. Here we explored the pharmacotherapeutic potential of IL‐17A for the treatmen...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201370/ https://www.ncbi.nlm.nih.gov/pubmed/30207057 http://dx.doi.org/10.1111/jcmm.13828 |
_version_ | 1783365484285001728 |
---|---|
author | Suyama, Kaori Sakai, Daisuke Hirayama, Noriaki Nakamura, Yoshihiko Matsushita, Erika Terayama, Hayato Qu, Ning Tanaka, Osamu Sakabe, Kou Watanabe, Masahiko |
author_facet | Suyama, Kaori Sakai, Daisuke Hirayama, Noriaki Nakamura, Yoshihiko Matsushita, Erika Terayama, Hayato Qu, Ning Tanaka, Osamu Sakabe, Kou Watanabe, Masahiko |
author_sort | Suyama, Kaori |
collection | PubMed |
description | Intervertebral discs (IVD) degeneration, which is caused by ageing or mechanical stress, leads to IVD disease, including back pain and sciatica. The cytokine interleukin (IL)‐17A is elevated in NP cells during IVD disease. Here we explored the pharmacotherapeutic potential of IL‐17A for the treatment of IVD disease using small‐molecule inhibitors that block binding of IL‐17A to the IL‐17A receptor (IL‐17RA). Treatment of NP cells with IL‐17A increased expression of cyclooxygenase‐2 (COX‐2), IL‐6, matrix metalloproteinase (MMP)‐3 and MMP‐13. These increases were suppressed by an IL‐17A‐neutralizing antibody, and small molecules that were identified as inhibitors by binding to the IL‐17A‐binding region of IL‐17RA. IL‐17A signalling also altered sulphated glycosaminoglycan deposition and spheroid colony formation, while treatment with small‐molecule inhibitors of IL‐17A attenuated this response. Furthermore, mitogen‐activated protein kinase pathways were activated by IL‐17A stimulation and induced IL‐6 and COX‐2 expression, while small‐molecule inhibitors of IL‐17A suppressed their expression. Taken together, these results show that IL‐17A is a valid target for IVD disease therapy and that small‐molecule inhibitors that inhibit the IL‐17A–IL‐17RA interaction may be useful for pharmacotherapy of IVD disease. |
format | Online Article Text |
id | pubmed-6201370 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-62013702018-11-01 Effects of interleukin‐17A in nucleus pulposus cells and its small‐molecule inhibitors for intervertebral disc disease Suyama, Kaori Sakai, Daisuke Hirayama, Noriaki Nakamura, Yoshihiko Matsushita, Erika Terayama, Hayato Qu, Ning Tanaka, Osamu Sakabe, Kou Watanabe, Masahiko J Cell Mol Med Original Articles Intervertebral discs (IVD) degeneration, which is caused by ageing or mechanical stress, leads to IVD disease, including back pain and sciatica. The cytokine interleukin (IL)‐17A is elevated in NP cells during IVD disease. Here we explored the pharmacotherapeutic potential of IL‐17A for the treatment of IVD disease using small‐molecule inhibitors that block binding of IL‐17A to the IL‐17A receptor (IL‐17RA). Treatment of NP cells with IL‐17A increased expression of cyclooxygenase‐2 (COX‐2), IL‐6, matrix metalloproteinase (MMP)‐3 and MMP‐13. These increases were suppressed by an IL‐17A‐neutralizing antibody, and small molecules that were identified as inhibitors by binding to the IL‐17A‐binding region of IL‐17RA. IL‐17A signalling also altered sulphated glycosaminoglycan deposition and spheroid colony formation, while treatment with small‐molecule inhibitors of IL‐17A attenuated this response. Furthermore, mitogen‐activated protein kinase pathways were activated by IL‐17A stimulation and induced IL‐6 and COX‐2 expression, while small‐molecule inhibitors of IL‐17A suppressed their expression. Taken together, these results show that IL‐17A is a valid target for IVD disease therapy and that small‐molecule inhibitors that inhibit the IL‐17A–IL‐17RA interaction may be useful for pharmacotherapy of IVD disease. John Wiley and Sons Inc. 2018-09-11 2018-11 /pmc/articles/PMC6201370/ /pubmed/30207057 http://dx.doi.org/10.1111/jcmm.13828 Text en © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Suyama, Kaori Sakai, Daisuke Hirayama, Noriaki Nakamura, Yoshihiko Matsushita, Erika Terayama, Hayato Qu, Ning Tanaka, Osamu Sakabe, Kou Watanabe, Masahiko Effects of interleukin‐17A in nucleus pulposus cells and its small‐molecule inhibitors for intervertebral disc disease |
title | Effects of interleukin‐17A in nucleus pulposus cells and its small‐molecule inhibitors for intervertebral disc disease |
title_full | Effects of interleukin‐17A in nucleus pulposus cells and its small‐molecule inhibitors for intervertebral disc disease |
title_fullStr | Effects of interleukin‐17A in nucleus pulposus cells and its small‐molecule inhibitors for intervertebral disc disease |
title_full_unstemmed | Effects of interleukin‐17A in nucleus pulposus cells and its small‐molecule inhibitors for intervertebral disc disease |
title_short | Effects of interleukin‐17A in nucleus pulposus cells and its small‐molecule inhibitors for intervertebral disc disease |
title_sort | effects of interleukin‐17a in nucleus pulposus cells and its small‐molecule inhibitors for intervertebral disc disease |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201370/ https://www.ncbi.nlm.nih.gov/pubmed/30207057 http://dx.doi.org/10.1111/jcmm.13828 |
work_keys_str_mv | AT suyamakaori effectsofinterleukin17ainnucleuspulposuscellsanditssmallmoleculeinhibitorsforintervertebraldiscdisease AT sakaidaisuke effectsofinterleukin17ainnucleuspulposuscellsanditssmallmoleculeinhibitorsforintervertebraldiscdisease AT hirayamanoriaki effectsofinterleukin17ainnucleuspulposuscellsanditssmallmoleculeinhibitorsforintervertebraldiscdisease AT nakamurayoshihiko effectsofinterleukin17ainnucleuspulposuscellsanditssmallmoleculeinhibitorsforintervertebraldiscdisease AT matsushitaerika effectsofinterleukin17ainnucleuspulposuscellsanditssmallmoleculeinhibitorsforintervertebraldiscdisease AT terayamahayato effectsofinterleukin17ainnucleuspulposuscellsanditssmallmoleculeinhibitorsforintervertebraldiscdisease AT quning effectsofinterleukin17ainnucleuspulposuscellsanditssmallmoleculeinhibitorsforintervertebraldiscdisease AT tanakaosamu effectsofinterleukin17ainnucleuspulposuscellsanditssmallmoleculeinhibitorsforintervertebraldiscdisease AT sakabekou effectsofinterleukin17ainnucleuspulposuscellsanditssmallmoleculeinhibitorsforintervertebraldiscdisease AT watanabemasahiko effectsofinterleukin17ainnucleuspulposuscellsanditssmallmoleculeinhibitorsforintervertebraldiscdisease |