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 deficien...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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The British Editorial Society of Bone & Joint Surgery
2022-07-01
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| Series: | Bone & Joint Research |
| Subjects: | |
| Online Access: | https://online.boneandjoint.org.uk/doi/epdf/10.1302/2046-3758.117.BJR-2021-0481.R1 |
| _version_ | 1811343093006336000 |
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| author | Silvia Hayer Birgit Niederreiter Marlene Kalkgruber Konrad Wanic Julia Maißner Josef S. Smolen Daniel Aletaha Stephan Blüml Kurt Redlich |
| author_facet | Silvia Hayer Birgit Niederreiter Marlene Kalkgruber Konrad Wanic Julia Maißner Josef S. Smolen Daniel Aletaha Stephan Blüml Kurt Redlich |
| author_sort | Silvia Hayer |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-13T19:22:33Z |
| format | Article |
| id | doaj.art-835e90a3276e4745b366d63999be6d4f |
| institution | Directory Open Access Journal |
| issn | 2046-3758 |
| language | English |
| last_indexed | 2024-04-13T19:22:33Z |
| publishDate | 2022-07-01 |
| publisher | The British Editorial Society of Bone & Joint Surgery |
| record_format | Article |
| series | Bone & Joint Research |
| spelling | doaj.art-835e90a3276e4745b366d63999be6d4f2022-12-22T02:33:28ZengThe British Editorial Society of Bone & Joint SurgeryBone & Joint Research2046-37582022-07-0111748449310.1302/2046-3758.117.BJR-2021-0481.R1Analysis of combined deficiency of interleukin-1 and -6 versus single deficiencies in TNF-mediated arthritis and systemic bone lossSilvia Hayer0Birgit Niederreiter1Marlene Kalkgruber2Konrad Wanic3Julia Maißner4Josef S. Smolen5Daniel Aletaha6Stephan Blüml7Kurt Redlich8Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, AustriaDepartment of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, AustriaDepartment of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, AustriaDepartment of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, AustriaDepartment of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, AustriaDepartment of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, AustriaDepartment of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, AustriaDepartment of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, AustriaDepartment of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, AustriaAims: 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.https://online.boneandjoint.org.uk/doi/epdf/10.1302/2046-3758.117.BJR-2021-0481.R1experimental arthritiscytokineinflammatory joint damageinflammatory systemic bone lossinterleukinarthritisosteopeniail-6cytokinestumour necrosis factorsacroiliitisinflammatory arthritismicro-ctjoint damage |
| spellingShingle | Silvia Hayer Birgit Niederreiter Marlene Kalkgruber Konrad Wanic Julia Maißner Josef S. Smolen Daniel Aletaha Stephan Blüml Kurt Redlich Analysis of combined deficiency of interleukin-1 and -6 versus single deficiencies in TNF-mediated arthritis and systemic bone loss Bone & Joint Research experimental arthritis cytokine inflammatory joint damage inflammatory systemic bone loss interleukin arthritis osteopenia il-6 cytokines tumour necrosis factor sacroiliitis inflammatory arthritis micro-ct joint damage |
| 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 | experimental arthritis cytokine inflammatory joint damage inflammatory systemic bone loss interleukin arthritis osteopenia il-6 cytokines tumour necrosis factor sacroiliitis inflammatory arthritis micro-ct joint damage |
| url | https://online.boneandjoint.org.uk/doi/epdf/10.1302/2046-3758.117.BJR-2021-0481.R1 |
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