Targeting the NF-κB signaling pathway in chronic tendon disease

Abraham, A. C. et al. (2019) Targeting the NF-κB signaling pathway in chronic tendon disease. Science Translational Medicine, 11(481), eaav4319. (doi: 10.1126/scitranslmed.aav4319) (PMID:30814338) (PMCID:PMC6534967)

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Abstract

Tendon disorders represent the most common musculoskeletal complaint for which patients seek medical attention; inflammation drives tendon degeneration before tearing and impairs healing after repair. Clinical evidence has implicated the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway as a correlate of pain-free return to function after surgical repair. However, it is currently unknown whether this response is a reaction to or a driver of pathology. Therefore, we aimed to understand the clinically relevant involvement of the NF-κB pathway in tendinopathy, to determine its potential causative roles in tendon degeneration, and to test its potential as a therapeutic candidate. Transcriptional profiling of early rotator cuff tendinopathy identified increases in NF-κB signaling, including increased expression of the regulatory serine kinase subunit IKKβ, which plays an essential role in inflammation. Using cre-mediated overexpression of IKKβ in tendon fibroblasts, we observed degeneration of mouse rotator cuff tendons and the adjacent humeral head. These changes were associated with increases in proinflammatory cytokines and innate immune cells within the joint. Conversely, genetic deletion of IKKβ in tendon fibroblasts partially protected mice from chronic overuse-induced tendinopathy. Furthermore, conditional knockout of IKKβ improved outcomes after surgical repair, whereas overexpression impaired tendon healing. Accordingly, targeting of the IKKβ/NF-κB pathway in tendon stromal cells may offer previously unidentified therapeutic approaches in the management of human tendon disorders.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Akbar, Mr Moeed and Millar, Dr Neal
Authors: Abraham, A. C., Shah, S. A., Golman, M., Song, L., Li, X., Kurtaliaj, I., Akbar, M., Millar, N. L., Abu-Amer, Y., Galatz, L. M., and Thomopoulos, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Science Translational Medicine
Publisher:American Association for the Advancement of Science
ISSN:1946-6234
ISSN (Online):1946-6242

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301515Damage mechanisms in tendon diseaseNeal MillarMedical Research Council (MRC)MR/R020515/1III - Immunology
173463HMGB1: a key damage mediator in tendinopathyNeal MillarVersus Arthritis (ARTRESUK)21346III - Immunology