The nuclear factor-κB (NF-κB) pathway is upregulated in tendon degeneration and injury, but whether this response is a cause or effect of tendon pathology is unclear. The findings of a new study suggest that IKKβ, a kinase that mediates NF-κB activation, contributes to tendinopathy in mice, and that blocking this pathway has therapeutic potential in humans.
“It was unclear from the literature whether inflammation was a good thing or a bad thing for tendinopathy.” explains corresponding author Stavros Thomopoulos. “On the one hand, high levels of inflammation can be damaging to the tendons. On the other hand, completing shutting down inflammation with broadly acting anti-inflammatory drugs can also be damaging.”
To investigate the underlying processes, Thomopoulos and colleagues focused their attention on the NF-κB pathway. They confirmed that components of this pathway, including IKK complex proteins, were upregulated in the tendons of patients with early-stage tendinopathy, compared with tendons from healthy individuals.
The researchers used a Cre–loxP system to selectively manipulate the expression of IKKβ in the tendon fibroblasts of mice. Constitutive activation of IKKβ lead to degeneration of the rotator cuff tendons (mimicking changes observed in the tendons of patients with rotator cuff disease), whereas deletion of IKKβ partially protected mice from tendinopathy in a chronic overuse-induced model and in a surgical model of tendon injury and repair.
To simulate human inflammatory tendinopathy in vitro, tendon fibroblasts from healthy individuals were incubated with IL-1β. In this model, treatment with an IKKβ inhibitor prevented NF-κB signalling and pro-inflammatory cytokine production.
treatment with an IKKβ inhibitor prevented NF-κB signalling and pro-inflammatory cytokine production
“We are currently testing this inhibitor in a rat rotator cuff model,” says Thomopoulos. “If successful, we hope to test the efficacy in a large animal model and ultimately in patients.”
Abraham, A. C. et al. Targeting the NF-κB signaling pathway in chronic tendon disease. Sci.Transl. Med. 11, eaav4319 (2019)
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McHugh, J. Targeting NF-κB in tendinopathy. Nat Rev Rheumatol 15, 251 (2019). https://doi.org/10.1038/s41584-019-0206-x