Targeting the IL-17A pathway for therapy in early-stage tendinopathy
Objectives Tendinopathy is a frequent clinical problem and represents an extraordinary health economic and socioeconomic burden with high unmet medical needs. Recent clinical evidence suggests blockade of interleukin 17A (IL-17A) for tendinopathy therapy. The present preclinical study elucidates the...
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BMJ Publishing Group
2025-02-01
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| Series: | RMD Open |
| Online Access: | https://rmdopen.bmj.com/content/11/1/e004729.full |
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| author | Iain B McInnes Richard M Siegel Neal L Millar Moeed Akbar Michaela Kneissel Frank Kolbinger Friedrich Raulf Yufei Li Nicolau Beckmann Nathalie Accart Olivier Leupin Claudio Calonder Matthias Schieker Christian Bruns Eckhard Weber |
| author_facet | Iain B McInnes Richard M Siegel Neal L Millar Moeed Akbar Michaela Kneissel Frank Kolbinger Friedrich Raulf Yufei Li Nicolau Beckmann Nathalie Accart Olivier Leupin Claudio Calonder Matthias Schieker Christian Bruns Eckhard Weber |
| author_sort | Iain B McInnes |
| collection | DOAJ |
| description | Objectives Tendinopathy is a frequent clinical problem and represents an extraordinary health economic and socioeconomic burden with high unmet medical needs. Recent clinical evidence suggests blockade of interleukin 17A (IL-17A) for tendinopathy therapy. The present preclinical study elucidates the biological mechanisms of IL-17A pathway stimulation and blockade in tendinopathy.Methods We explored whether IL-17A and other IL-17 family members are differentially expressed in biopsies of healthy, early-stage and late-stage tendinopathic human rotator cuff tendons using RT-qPCR. IL-17 pathway signature genes in healthy human tendon-derived cells were identified following IL-17A stimulation using AmpliSeq RNA. The molecular, structural and functional consequences of IL-17A pathway stimulation were explored in healthy human tendon-derived cells and in a rat tendon fascicle model ex vivo. The effects of IL-17A pathway blockade were investigated in a rat model of rotator cuff tendinopathy in vivo.Results We provide evidence of differential expression of IL-17A mRNA (IL17A) versus other IL-17 family members in human rotator cuff early-stage tendinopathy. In human tendon-derived cells, stimulation with IL-17A induced the expression of the selected IL-17A pathway signature genes NFKBIZ, ZC3H12A, CXCL1, IL6, MMP3. Expression was inhibited by IL-17A blockade. In the rat ex vivo and in vivo models, IL-17A blockade alleviated inflammatory immune effector release, tendon structural degeneration, tendon inflammation and impaired tendon function.Conclusion Our data provide evidence that IL-17A is a key contributor to the pathogenesis of tendinopathy by promoting tendon inflammation and degeneration and that IL-17A blockade may represent a potential therapy in early-stage tendinopathy. |
| format | Article |
| id | doaj-art-d7de2a47d7cb451a8a6ed9d1ab3648d3 |
| institution | DOAJ |
| issn | 2056-5933 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | RMD Open |
| spelling | doaj-art-d7de2a47d7cb451a8a6ed9d1ab3648d32025-08-20T02:45:09ZengBMJ Publishing GroupRMD Open2056-59332025-02-0111110.1136/rmdopen-2024-004729Targeting the IL-17A pathway for therapy in early-stage tendinopathyIain B McInnes0Richard M Siegel1Neal L Millar2Moeed Akbar3Michaela Kneissel4Frank Kolbinger5Friedrich Raulf6Yufei Li7Nicolau Beckmann8Nathalie Accart9Olivier Leupin10Claudio Calonder11Matthias Schieker12Christian Bruns13Eckhard Weber1419 MVLS College Office, University of Glasgow, Glasgow, UKNovartis Pharma AG, Biomedical Research, Basel, SwitzerlandInstitute of Infection, Immunity and Inflammation, College of Medicine,Veterinary and Life Sciences, University of Glasgow, Glasgow, UK1 Institute of Infection, Immunity and Inflammation, University of Glasgow College of Medical Veterinary and Life Sciences, Glasgow, UKNovartis Institutes for BioMedical Research, Basel, SwitzerlandAutoimmunity, Transplantation and Inflammation Disease Area, Novartis Institutes for BioMedical Research, Basel, SwitzerlandNovartis Pharma AG, Biomedical Research, Basel, SwitzerlandNovartis Pharma AG, Biomedical Research, Basel, SwitzerlandNovartis Pharma AG, Biomedical Research, Basel, SwitzerlandNovartis Pharma AG, Biomedical Research, Basel, SwitzerlandNovartis Pharma AG, Biomedical Research, Basel, SwitzerlandNovartis Pharma AG, Biomedical Research, Basel, SwitzerlandNovartis Pharma AG, Biomedical Research, Basel, SwitzerlandNovartis Pharma AG, Biomedical Research, Basel, SwitzerlandNovartis Pharma AG, Biomedical Research, Basel, SwitzerlandObjectives Tendinopathy is a frequent clinical problem and represents an extraordinary health economic and socioeconomic burden with high unmet medical needs. Recent clinical evidence suggests blockade of interleukin 17A (IL-17A) for tendinopathy therapy. The present preclinical study elucidates the biological mechanisms of IL-17A pathway stimulation and blockade in tendinopathy.Methods We explored whether IL-17A and other IL-17 family members are differentially expressed in biopsies of healthy, early-stage and late-stage tendinopathic human rotator cuff tendons using RT-qPCR. IL-17 pathway signature genes in healthy human tendon-derived cells were identified following IL-17A stimulation using AmpliSeq RNA. The molecular, structural and functional consequences of IL-17A pathway stimulation were explored in healthy human tendon-derived cells and in a rat tendon fascicle model ex vivo. The effects of IL-17A pathway blockade were investigated in a rat model of rotator cuff tendinopathy in vivo.Results We provide evidence of differential expression of IL-17A mRNA (IL17A) versus other IL-17 family members in human rotator cuff early-stage tendinopathy. In human tendon-derived cells, stimulation with IL-17A induced the expression of the selected IL-17A pathway signature genes NFKBIZ, ZC3H12A, CXCL1, IL6, MMP3. Expression was inhibited by IL-17A blockade. In the rat ex vivo and in vivo models, IL-17A blockade alleviated inflammatory immune effector release, tendon structural degeneration, tendon inflammation and impaired tendon function.Conclusion Our data provide evidence that IL-17A is a key contributor to the pathogenesis of tendinopathy by promoting tendon inflammation and degeneration and that IL-17A blockade may represent a potential therapy in early-stage tendinopathy.https://rmdopen.bmj.com/content/11/1/e004729.full |
| spellingShingle | Iain B McInnes Richard M Siegel Neal L Millar Moeed Akbar Michaela Kneissel Frank Kolbinger Friedrich Raulf Yufei Li Nicolau Beckmann Nathalie Accart Olivier Leupin Claudio Calonder Matthias Schieker Christian Bruns Eckhard Weber Targeting the IL-17A pathway for therapy in early-stage tendinopathy RMD Open |
| title | Targeting the IL-17A pathway for therapy in early-stage tendinopathy |
| title_full | Targeting the IL-17A pathway for therapy in early-stage tendinopathy |
| title_fullStr | Targeting the IL-17A pathway for therapy in early-stage tendinopathy |
| title_full_unstemmed | Targeting the IL-17A pathway for therapy in early-stage tendinopathy |
| title_short | Targeting the IL-17A pathway for therapy in early-stage tendinopathy |
| title_sort | targeting the il 17a pathway for therapy in early stage tendinopathy |
| url | https://rmdopen.bmj.com/content/11/1/e004729.full |
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