Cargando…

Inhibition of histone deacetylase 6 suppresses inflammatory responses and invasiveness of fibroblast-like-synoviocytes in inflammatory arthritis

BACKGROUND: To investigate the effects of inhibiting histone deacetylase (HDAC) 6 on inflammatory responses and tissue-destructive functions of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). METHODS: FLS from RA patients were activated with interleukin (IL)-1β in the presence of in...

Descripción completa

Detalles Bibliográficos
Autores principales: Park, Jin Kyun, Shon, Sehui, Yoo, Hyun Jung, Suh, Dong-Hyeon, Bae, Daekwon, Shin, Jieun, Jun, Jae Hyun, Ha, Nina, Song, Hyeseung, Choi, Young Il, Pap, Thomas, Song, Yeong Wook
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256575/
https://www.ncbi.nlm.nih.gov/pubmed/34225810
http://dx.doi.org/10.1186/s13075-021-02561-4
_version_ 1783718126154678272
author Park, Jin Kyun
Shon, Sehui
Yoo, Hyun Jung
Suh, Dong-Hyeon
Bae, Daekwon
Shin, Jieun
Jun, Jae Hyun
Ha, Nina
Song, Hyeseung
Choi, Young Il
Pap, Thomas
Song, Yeong Wook
author_facet Park, Jin Kyun
Shon, Sehui
Yoo, Hyun Jung
Suh, Dong-Hyeon
Bae, Daekwon
Shin, Jieun
Jun, Jae Hyun
Ha, Nina
Song, Hyeseung
Choi, Young Il
Pap, Thomas
Song, Yeong Wook
author_sort Park, Jin Kyun
collection PubMed
description BACKGROUND: To investigate the effects of inhibiting histone deacetylase (HDAC) 6 on inflammatory responses and tissue-destructive functions of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). METHODS: FLS from RA patients were activated with interleukin (IL)-1β in the presence of increasing concentrations of M808, a novel specific HDAC6 inhibitor. Production of ILs, chemokines, and metalloproteinases (MMPs) was measured in ELISAs. Acetylation of tubulin and expression of ICAM-1 and VCAM-1 were assessed by Western blotting. Wound healing and adhesion assays were performed. Cytoskeletal organization was visualized by immunofluorescence. Finally, the impact of HDAC6 inhibition on the severity of arthritis and joint histology was examined in a murine model of adjuvant-induced arthritis (AIA). RESULTS: HDAC6 was selectively inhibited by M808. The HDAC6 inhibitor suppressed the production of MMP-1, MMP-3, IL-6, CCL2, CXCL8, and CXCL10 by RA-FLS in response to IL-1β. Increased acetylation of tubulin was associated with decreased migration of RA-FLS. Inhibiting HDAC6 induced cytoskeletal reorganization in RA-FLS by suppressing the formation of invadopodia following activation with IL-1β. In addition, M808 tended to decrease the expression of ICAM-1 and VCAM-1. In the AIA arthritis model, M808 improved the clinical arthritis score in a dose-dependent manner. Also, HDAC6 inhibition was associated with less severe synovial inflammation and joint destruction. CONCLUSION: Inhibiting HDAC6 dampens the inflammatory and destructive activity of RA-FLS and reduces the severity of arthritis. Thus, targeting HDAC6 has therapeutic potential.
format Online
Article
Text
id pubmed-8256575
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-82565752021-07-06 Inhibition of histone deacetylase 6 suppresses inflammatory responses and invasiveness of fibroblast-like-synoviocytes in inflammatory arthritis Park, Jin Kyun Shon, Sehui Yoo, Hyun Jung Suh, Dong-Hyeon Bae, Daekwon Shin, Jieun Jun, Jae Hyun Ha, Nina Song, Hyeseung Choi, Young Il Pap, Thomas Song, Yeong Wook Arthritis Res Ther Research Article BACKGROUND: To investigate the effects of inhibiting histone deacetylase (HDAC) 6 on inflammatory responses and tissue-destructive functions of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). METHODS: FLS from RA patients were activated with interleukin (IL)-1β in the presence of increasing concentrations of M808, a novel specific HDAC6 inhibitor. Production of ILs, chemokines, and metalloproteinases (MMPs) was measured in ELISAs. Acetylation of tubulin and expression of ICAM-1 and VCAM-1 were assessed by Western blotting. Wound healing and adhesion assays were performed. Cytoskeletal organization was visualized by immunofluorescence. Finally, the impact of HDAC6 inhibition on the severity of arthritis and joint histology was examined in a murine model of adjuvant-induced arthritis (AIA). RESULTS: HDAC6 was selectively inhibited by M808. The HDAC6 inhibitor suppressed the production of MMP-1, MMP-3, IL-6, CCL2, CXCL8, and CXCL10 by RA-FLS in response to IL-1β. Increased acetylation of tubulin was associated with decreased migration of RA-FLS. Inhibiting HDAC6 induced cytoskeletal reorganization in RA-FLS by suppressing the formation of invadopodia following activation with IL-1β. In addition, M808 tended to decrease the expression of ICAM-1 and VCAM-1. In the AIA arthritis model, M808 improved the clinical arthritis score in a dose-dependent manner. Also, HDAC6 inhibition was associated with less severe synovial inflammation and joint destruction. CONCLUSION: Inhibiting HDAC6 dampens the inflammatory and destructive activity of RA-FLS and reduces the severity of arthritis. Thus, targeting HDAC6 has therapeutic potential. BioMed Central 2021-07-05 2021 /pmc/articles/PMC8256575/ /pubmed/34225810 http://dx.doi.org/10.1186/s13075-021-02561-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Park, Jin Kyun
Shon, Sehui
Yoo, Hyun Jung
Suh, Dong-Hyeon
Bae, Daekwon
Shin, Jieun
Jun, Jae Hyun
Ha, Nina
Song, Hyeseung
Choi, Young Il
Pap, Thomas
Song, Yeong Wook
Inhibition of histone deacetylase 6 suppresses inflammatory responses and invasiveness of fibroblast-like-synoviocytes in inflammatory arthritis
title Inhibition of histone deacetylase 6 suppresses inflammatory responses and invasiveness of fibroblast-like-synoviocytes in inflammatory arthritis
title_full Inhibition of histone deacetylase 6 suppresses inflammatory responses and invasiveness of fibroblast-like-synoviocytes in inflammatory arthritis
title_fullStr Inhibition of histone deacetylase 6 suppresses inflammatory responses and invasiveness of fibroblast-like-synoviocytes in inflammatory arthritis
title_full_unstemmed Inhibition of histone deacetylase 6 suppresses inflammatory responses and invasiveness of fibroblast-like-synoviocytes in inflammatory arthritis
title_short Inhibition of histone deacetylase 6 suppresses inflammatory responses and invasiveness of fibroblast-like-synoviocytes in inflammatory arthritis
title_sort inhibition of histone deacetylase 6 suppresses inflammatory responses and invasiveness of fibroblast-like-synoviocytes in inflammatory arthritis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256575/
https://www.ncbi.nlm.nih.gov/pubmed/34225810
http://dx.doi.org/10.1186/s13075-021-02561-4
work_keys_str_mv AT parkjinkyun inhibitionofhistonedeacetylase6suppressesinflammatoryresponsesandinvasivenessoffibroblastlikesynoviocytesininflammatoryarthritis
AT shonsehui inhibitionofhistonedeacetylase6suppressesinflammatoryresponsesandinvasivenessoffibroblastlikesynoviocytesininflammatoryarthritis
AT yoohyunjung inhibitionofhistonedeacetylase6suppressesinflammatoryresponsesandinvasivenessoffibroblastlikesynoviocytesininflammatoryarthritis
AT suhdonghyeon inhibitionofhistonedeacetylase6suppressesinflammatoryresponsesandinvasivenessoffibroblastlikesynoviocytesininflammatoryarthritis
AT baedaekwon inhibitionofhistonedeacetylase6suppressesinflammatoryresponsesandinvasivenessoffibroblastlikesynoviocytesininflammatoryarthritis
AT shinjieun inhibitionofhistonedeacetylase6suppressesinflammatoryresponsesandinvasivenessoffibroblastlikesynoviocytesininflammatoryarthritis
AT junjaehyun inhibitionofhistonedeacetylase6suppressesinflammatoryresponsesandinvasivenessoffibroblastlikesynoviocytesininflammatoryarthritis
AT hanina inhibitionofhistonedeacetylase6suppressesinflammatoryresponsesandinvasivenessoffibroblastlikesynoviocytesininflammatoryarthritis
AT songhyeseung inhibitionofhistonedeacetylase6suppressesinflammatoryresponsesandinvasivenessoffibroblastlikesynoviocytesininflammatoryarthritis
AT choiyoungil inhibitionofhistonedeacetylase6suppressesinflammatoryresponsesandinvasivenessoffibroblastlikesynoviocytesininflammatoryarthritis
AT papthomas inhibitionofhistonedeacetylase6suppressesinflammatoryresponsesandinvasivenessoffibroblastlikesynoviocytesininflammatoryarthritis
AT songyeongwook inhibitionofhistonedeacetylase6suppressesinflammatoryresponsesandinvasivenessoffibroblastlikesynoviocytesininflammatoryarthritis