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Analysis of combined deficiency of interleukin-1 and -6 versus single deficiencies in TNF-mediated arthritis and systemic bone loss
AIMS: Insufficient treatment response in rheumatoid arthritis (RA) patients requires novel treatment strategies to halt disease progression. The potential benefit of combination of cytokine-inhibitors in RA is still unclear and needs further investigation. To explore the impact of combined deficienc...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The British Editorial Society of Bone & Joint Surgery
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9350695/ https://www.ncbi.nlm.nih.gov/pubmed/35801532 http://dx.doi.org/10.1302/2046-3758.117.BJR-2021-0481.R1 |
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author | Hayer, Silvia Niederreiter, Birgit Kalkgruber, Marlene Wanic, Konrad Maißner, Julia Smolen, Josef S. Aletaha, Daniel Blüml, Stephan Redlich, Kurt |
author_facet | Hayer, Silvia Niederreiter, Birgit Kalkgruber, Marlene Wanic, Konrad Maißner, Julia Smolen, Josef S. Aletaha, Daniel Blüml, Stephan Redlich, Kurt |
author_sort | Hayer, Silvia |
collection | PubMed |
description | AIMS: Insufficient treatment response in rheumatoid arthritis (RA) patients requires novel treatment strategies to halt disease progression. The potential benefit of combination of cytokine-inhibitors in RA is still unclear and needs further investigation. To explore the impact of combined deficiency of two major cytokines, namely interleukin (IL)-1 and IL-6, in this study double deficient mice for IL-1αβ and IL-6 were investigated in different tumour necrosis factor (TNF)-driven inflammatory bone disorders, namely peripheral arthritis and sacroiliitis, as well as systemic bone loss. METHODS: Disease course, histopathological features of arthritis, and micro-CT (µCT) bone analysis of local and systemic bone loss were assessed in 15-week-old IL1(-/-)IL6(-/-) hTNFtg in comparison to IL1(-/-) hTNFtg, IL6(-/-) hTNFtg, and hTNFtg mice. µCT bone analysis of single deficient and wild-type mice was also performed. RESULTS: Combined deficiency of IL-1/IL-6 markedly ameliorated TNF-mediated arthritis and bilateral sacroiliitis, but without additive benefits compared to single IL-1 deficiency. This finding confirms the important role of IL-1 and the marginal role of IL-6 in TNF-driven pathways of local joint damage, but questions the efficacy of potential combinatorial therapies of IL-1 and IL-6 in treatment of RA. In contrast, combined deficiency of IL-1/IL-6 led to an additive protective effect on TNF-driven systemic bone loss compared to single IL-1 and IL-6 deficiency. This finding clearly indicates a common contribution of both IL-1 and IL-6 in TNF-driven systemic bone loss, and points to a discrepancy of cytokine dependency in local and systemic TNF-driven mechanisms of inflammatory arthritis. CONCLUSION: Combinatorial treatments in RA might provide different benefits to inflammatory local arthritis and systemic comorbidities. Cite this article: Bone Joint Res 2022;11(7):484–493. |
format | Online Article Text |
id | pubmed-9350695 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | The British Editorial Society of Bone & Joint Surgery |
record_format | MEDLINE/PubMed |
spelling | pubmed-93506952022-08-15 Analysis of combined deficiency of interleukin-1 and -6 versus single deficiencies in TNF-mediated arthritis and systemic bone loss Hayer, Silvia Niederreiter, Birgit Kalkgruber, Marlene Wanic, Konrad Maißner, Julia Smolen, Josef S. Aletaha, Daniel Blüml, Stephan Redlich, Kurt Bone Joint Res Arthritis AIMS: Insufficient treatment response in rheumatoid arthritis (RA) patients requires novel treatment strategies to halt disease progression. The potential benefit of combination of cytokine-inhibitors in RA is still unclear and needs further investigation. To explore the impact of combined deficiency of two major cytokines, namely interleukin (IL)-1 and IL-6, in this study double deficient mice for IL-1αβ and IL-6 were investigated in different tumour necrosis factor (TNF)-driven inflammatory bone disorders, namely peripheral arthritis and sacroiliitis, as well as systemic bone loss. METHODS: Disease course, histopathological features of arthritis, and micro-CT (µCT) bone analysis of local and systemic bone loss were assessed in 15-week-old IL1(-/-)IL6(-/-) hTNFtg in comparison to IL1(-/-) hTNFtg, IL6(-/-) hTNFtg, and hTNFtg mice. µCT bone analysis of single deficient and wild-type mice was also performed. RESULTS: Combined deficiency of IL-1/IL-6 markedly ameliorated TNF-mediated arthritis and bilateral sacroiliitis, but without additive benefits compared to single IL-1 deficiency. This finding confirms the important role of IL-1 and the marginal role of IL-6 in TNF-driven pathways of local joint damage, but questions the efficacy of potential combinatorial therapies of IL-1 and IL-6 in treatment of RA. In contrast, combined deficiency of IL-1/IL-6 led to an additive protective effect on TNF-driven systemic bone loss compared to single IL-1 and IL-6 deficiency. This finding clearly indicates a common contribution of both IL-1 and IL-6 in TNF-driven systemic bone loss, and points to a discrepancy of cytokine dependency in local and systemic TNF-driven mechanisms of inflammatory arthritis. CONCLUSION: Combinatorial treatments in RA might provide different benefits to inflammatory local arthritis and systemic comorbidities. Cite this article: Bone Joint Res 2022;11(7):484–493. The British Editorial Society of Bone & Joint Surgery 2022-07-13 /pmc/articles/PMC9350695/ /pubmed/35801532 http://dx.doi.org/10.1302/2046-3758.117.BJR-2021-0481.R1 Text en © 2022 Author(s) et al. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND 4.0) licence, which permits the copying and redistribution of the work only, and provided the original author and source are credited. See https://creativecommons.org/licenses/by-nc-nd/4.0/ |
spellingShingle | Arthritis Hayer, Silvia Niederreiter, Birgit Kalkgruber, Marlene Wanic, Konrad Maißner, Julia Smolen, Josef S. Aletaha, Daniel Blüml, Stephan Redlich, Kurt Analysis of combined deficiency of interleukin-1 and -6 versus single deficiencies in TNF-mediated arthritis and systemic bone loss |
title | Analysis of combined deficiency of interleukin-1 and -6 versus single deficiencies in TNF-mediated arthritis and systemic bone loss |
title_full | Analysis of combined deficiency of interleukin-1 and -6 versus single deficiencies in TNF-mediated arthritis and systemic bone loss |
title_fullStr | Analysis of combined deficiency of interleukin-1 and -6 versus single deficiencies in TNF-mediated arthritis and systemic bone loss |
title_full_unstemmed | Analysis of combined deficiency of interleukin-1 and -6 versus single deficiencies in TNF-mediated arthritis and systemic bone loss |
title_short | Analysis of combined deficiency of interleukin-1 and -6 versus single deficiencies in TNF-mediated arthritis and systemic bone loss |
title_sort | analysis of combined deficiency of interleukin-1 and -6 versus single deficiencies in tnf-mediated arthritis and systemic bone loss |
topic | Arthritis |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9350695/ https://www.ncbi.nlm.nih.gov/pubmed/35801532 http://dx.doi.org/10.1302/2046-3758.117.BJR-2021-0481.R1 |
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