Research ArticleTENDINOPATHY

Targeting the NF-κB signaling pathway in chronic tendon disease

See allHide authors and affiliations

Science Translational Medicine  27 Feb 2019:
Vol. 11, Issue 481, eaav4319
DOI: 10.1126/scitranslmed.aav4319

Targeting tendinopathy

Inflammation and NF-κB signaling contribute to tendon degeneration and injury, such as rotator cuff injury. Abraham et al. investigated how this signaling pathway causes tendinopathy and potential therapeutic effects of inhibiting the pathway. Clinical tendon samples of human rotator cuff disease showed up-regulation of NF-κB, which was mimicked in mouse tendon fibroblasts overexpressing IKKβ. Genetic deletion of IKKβ in tendon in mice prevented maladaptive tendon remodeling in a treadmill running–induced overuse tendinopathy model and in a surgical model of tendon injury and repair, and human tendon stromal cells treated with an IKKβ inhibitor showed repressed NF-κB target gene transcription. These results suggest that there may be therapeutic potential in blocking IKKβ.


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.

View Full Text

Stay Connected to Science Translational Medicine