Targeting the NF-κB Signaling Pathway in Chronic Tendon Disease

Sci Transl Med. 2019 Feb 27;11(481):eaav4319. doi: 10.1126/scitranslmed.aav4319.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adult
  • Animals
  • Chronic Disease
  • Cytokines / metabolism
  • Female
  • Fibroblasts / pathology
  • Humans
  • I-kappa B Kinase / metabolism
  • Male
  • Mice
  • Middle Aged
  • NF-kappa B / metabolism*
  • Signal Transduction*
  • Small Molecule Libraries / pharmacology
  • Stromal Cells / metabolism
  • Tendons / metabolism*
  • Tendons / pathology*
  • Wound Healing
  • Young Adult

Substances

  • Cytokines
  • NF-kappa B
  • Small Molecule Libraries
  • I-kappa B Kinase