Ets-2 Propagates IL-6 Trans-Signaling Mediated Osteoclast-Like Changes in Human Rheumatoid Arthritis Synovial Fibroblast

Rheumatoid arthritis synovial fibroblasts (RASFs) contribute to synovial inflammation and bone destruction by producing a pleiotropic cytokine interleukin-6 (IL-6). However, the molecular mechanisms through which IL-6 propels RASFs to contribute to bone loss are not fully understood. In the present...

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Autores principales:	Anil K. Singh, Mahamudul Haque, Bhanupriya Madarampalli, Yuanyuan Shi, Benjamin J. Wildman, Abdul Basit, Sadik A. Khuder, Bhagwat Prasad, Quamarul Hassan, Madhu M. Ouseph, Salahuddin Ahmed
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	osteoclast interleukin-6 synovial fibroblasts rheumatoid arthritis reprogramming Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/235e6e57e302480c915e68cbf27cff6c
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spelling	oai:doaj.org-article:235e6e57e302480c915e68cbf27cff6c2021-12-01T09:11:32ZEts-2 Propagates IL-6 Trans-Signaling Mediated Osteoclast-Like Changes in Human Rheumatoid Arthritis Synovial Fibroblast1664-322410.3389/fimmu.2021.746503https://doaj.org/article/235e6e57e302480c915e68cbf27cff6c2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.746503/fullhttps://doaj.org/toc/1664-3224Rheumatoid arthritis synovial fibroblasts (RASFs) contribute to synovial inflammation and bone destruction by producing a pleiotropic cytokine interleukin-6 (IL-6). However, the molecular mechanisms through which IL-6 propels RASFs to contribute to bone loss are not fully understood. In the present study, we investigated the effect of IL-6 and IL-6 receptor (IL-6/IL-6R)-induced trans-signaling in human RASFs. IL-6 trans-signaling caused a significant increase in tartrate-resistant acid phosphatase (TRAP)-positive staining in RASFs and enhanced pit formation by ~3-fold in the osteogenic surface in vitro. IL-6/IL-6R caused dose-dependent increase in expression and nuclear translocation of transcription factor Ets2, which correlated with the expression of osteoclast-specific signature proteins RANKL, cathepsin B (CTSB), and cathepsin K (CTSK) in RASFs. Chromatin immunoprecipitation (ChIP) analysis of CTSB and CTSK promoters showed direct Ets2 binding and transcriptional activation upon IL-6/IL-6R stimulation. Knockdown of Ets2 significantly inhibited IL-6/IL-6R-induced RANKL, CTSB, and CTSK expression and TRAP staining in RASFs and suppressed markers of RASF invasive phenotype such as Thy1 and podoplanin (PDPN). Mass spectrometry analysis of the secretome identified 113 proteins produced by RASFs uniquely in response to IL-6/IL-6R that bioinformatically predicted its impact on metabolic reprogramming towards an osteoclast-like phenotype. These findings identified the role of Ets2 in IL-6 trans-signaling induced molecular reprogramming of RASFs to osteoclast-like cells and may contribute to RASF heterogeneity.Anil K. SinghMahamudul HaqueBhanupriya MadarampalliYuanyuan ShiBenjamin J. WildmanAbdul BasitSadik A. KhuderBhagwat PrasadQuamarul HassanMadhu M. OusephSalahuddin AhmedSalahuddin AhmedFrontiers Media S.A.articleosteoclastinterleukin-6synovial fibroblastsrheumatoid arthritisreprogrammingImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	osteoclast interleukin-6 synovial fibroblasts rheumatoid arthritis reprogramming Immunologic diseases. Allergy RC581-607
spellingShingle	osteoclast interleukin-6 synovial fibroblasts rheumatoid arthritis reprogramming Immunologic diseases. Allergy RC581-607 Anil K. Singh Mahamudul Haque Bhanupriya Madarampalli Yuanyuan Shi Benjamin J. Wildman Abdul Basit Sadik A. Khuder Bhagwat Prasad Quamarul Hassan Madhu M. Ouseph Salahuddin Ahmed Salahuddin Ahmed Ets-2 Propagates IL-6 Trans-Signaling Mediated Osteoclast-Like Changes in Human Rheumatoid Arthritis Synovial Fibroblast
description	Rheumatoid arthritis synovial fibroblasts (RASFs) contribute to synovial inflammation and bone destruction by producing a pleiotropic cytokine interleukin-6 (IL-6). However, the molecular mechanisms through which IL-6 propels RASFs to contribute to bone loss are not fully understood. In the present study, we investigated the effect of IL-6 and IL-6 receptor (IL-6/IL-6R)-induced trans-signaling in human RASFs. IL-6 trans-signaling caused a significant increase in tartrate-resistant acid phosphatase (TRAP)-positive staining in RASFs and enhanced pit formation by ~3-fold in the osteogenic surface in vitro. IL-6/IL-6R caused dose-dependent increase in expression and nuclear translocation of transcription factor Ets2, which correlated with the expression of osteoclast-specific signature proteins RANKL, cathepsin B (CTSB), and cathepsin K (CTSK) in RASFs. Chromatin immunoprecipitation (ChIP) analysis of CTSB and CTSK promoters showed direct Ets2 binding and transcriptional activation upon IL-6/IL-6R stimulation. Knockdown of Ets2 significantly inhibited IL-6/IL-6R-induced RANKL, CTSB, and CTSK expression and TRAP staining in RASFs and suppressed markers of RASF invasive phenotype such as Thy1 and podoplanin (PDPN). Mass spectrometry analysis of the secretome identified 113 proteins produced by RASFs uniquely in response to IL-6/IL-6R that bioinformatically predicted its impact on metabolic reprogramming towards an osteoclast-like phenotype. These findings identified the role of Ets2 in IL-6 trans-signaling induced molecular reprogramming of RASFs to osteoclast-like cells and may contribute to RASF heterogeneity.
format	article
author	Anil K. Singh Mahamudul Haque Bhanupriya Madarampalli Yuanyuan Shi Benjamin J. Wildman Abdul Basit Sadik A. Khuder Bhagwat Prasad Quamarul Hassan Madhu M. Ouseph Salahuddin Ahmed Salahuddin Ahmed
author_facet	Anil K. Singh Mahamudul Haque Bhanupriya Madarampalli Yuanyuan Shi Benjamin J. Wildman Abdul Basit Sadik A. Khuder Bhagwat Prasad Quamarul Hassan Madhu M. Ouseph Salahuddin Ahmed Salahuddin Ahmed
author_sort	Anil K. Singh
title	Ets-2 Propagates IL-6 Trans-Signaling Mediated Osteoclast-Like Changes in Human Rheumatoid Arthritis Synovial Fibroblast
title_short	Ets-2 Propagates IL-6 Trans-Signaling Mediated Osteoclast-Like Changes in Human Rheumatoid Arthritis Synovial Fibroblast
title_full	Ets-2 Propagates IL-6 Trans-Signaling Mediated Osteoclast-Like Changes in Human Rheumatoid Arthritis Synovial Fibroblast
title_fullStr	Ets-2 Propagates IL-6 Trans-Signaling Mediated Osteoclast-Like Changes in Human Rheumatoid Arthritis Synovial Fibroblast
title_full_unstemmed	Ets-2 Propagates IL-6 Trans-Signaling Mediated Osteoclast-Like Changes in Human Rheumatoid Arthritis Synovial Fibroblast
title_sort	ets-2 propagates il-6 trans-signaling mediated osteoclast-like changes in human rheumatoid arthritis synovial fibroblast
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/235e6e57e302480c915e68cbf27cff6c
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Ets-2 Propagates IL-6 Trans-Signaling Mediated Osteoclast-Like Changes in Human Rheumatoid Arthritis Synovial Fibroblast

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