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Published on: August 1, 2020
Targeting the IL-17A pathway for therapy in early-stage tendinopathy
Neal L Millar1, Iain B McInnes2, Frank Kolbinger3
1School of Infection and Immunity, University of Glasgow, Glasgow, UK neal.millar@glasgow.ac.uk.
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.
Insights
Interleukin 17A (IL-17A) drives tendinopathy by promoting inflammation and degeneration. Blocking the IL-17A pathway shows potential as a therapeutic strategy for early-stage tendinopathy.
Area of Science:
- Immunology
- Orthopedics
- Molecular Biology
Background:
- Tendinopathy presents a significant clinical and socioeconomic challenge with limited treatment options.
- Interleukin 17A (IL-17A) is implicated in tendinopathy pathogenesis.
- Understanding the IL-17A pathway's role is crucial for developing novel therapies.
Purpose of the Study:
- To elucidate the biological mechanisms of IL-17A pathway stimulation and blockade in tendinopathy.
- To investigate the differential expression of IL-17 family members in human rotator cuff tendinopathy.
- To evaluate the therapeutic potential of IL-17A blockade.
Main Methods:
- RT-qPCR analysis of IL-17 family member expression in human rotator cuff tendon biopsies.
- IL-17A stimulation of human tendon-derived cells to identify pathway signature genes.
- Ex vivo and in vivo studies in rat models to assess IL-17A pathway blockade effects.
Main Results:
- Differential expression of IL-17A observed in early-stage human tendinopathy.
- IL-17A stimulation upregulated key inflammatory and matrix-degrading genes.
- IL-17A blockade in rat models reduced inflammation, structural damage, and improved function.
Conclusions:
- IL-17A is a critical mediator of tendon inflammation and degeneration in tendinopathy.
- IL-17A blockade demonstrates therapeutic promise for early-stage tendinopathy.
- Targeting the IL-17A pathway offers a potential new treatment strategy.
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