Research ArticleTissue Repair

NF-κB activation persists into the remodeling phase of tendon healing and promotes myofibroblast survival

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Science Signaling  17 Nov 2020:
Vol. 13, Issue 658, eabb7209
DOI: 10.1126/scisignal.abb7209

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NF-κB signaling in tendon repair

Tendon injuries usually heal through a fibrotic process, generating scar tissue that impairs the function of the healed tendon. The organized bundles of collagen and other extracellular matrix proteins that make up the bulk of tendon tissue are generated by proteins secreted by fibroblast-like cells called tenocytes. Best et al. found that nuclear factor κB (NF-κB) signaling not only was activated during the early inflammatory phase of flexor tendon healing in mice but also persisted into the late remodeling phases of repair in tenocytes and myofibroblasts. Reducing NF-κB signaling in tenocytes stimulated apoptosis and scarring during the late stages of healing. In human tendon scar tissue, NF-κB signaling was also active, and myofibroblasts expressed prosurvival markers. Thus, NF-κB signaling promotes cell survival and fibrotic progression during tendon healing.

Abstract

Although inflammation is necessary during the early phases of tissue repair, persistent inflammation contributes to fibrosis. Acute tendon injuries often heal through a fibrotic mechanism, which impedes regeneration and functional recovery. Because inflammation mediated by nuclear factor κB (NF-κB) signaling is implicated in this process, we examined the spatial, temporal, and cell type–specific activation profile of canonical NF-κB signaling during tendon healing. NF-κB signaling was maintained through all phases of tendon healing in mice, including the remodeling phase, and tenocytes and myofibroblasts from the Scleraxis (Scx) lineage were the predominant populations that retained NF-κB activation into the late stages of repair. We confirmed persistent NF-κB activation in myofibroblasts in human tendon scar tissue. Deleting the canonical NF-κB kinase, IKKβ, in Scx-lineage cells in mice increased apoptosis and the deposition of the matrix protein periostin during the late stages of tendon repair, suggesting that persistent NF-κB signaling may facilitate myofibroblast survival and fibrotic progression. Consistent with this, myofibroblasts in human tendon scar samples displayed enhanced prosurvival signaling compared to control tissue. Together, these data suggest that NF-κB may contribute to fibrotic tendon healing through both inflammation-dependent and inflammation-independent functions, such as NF-κB–mediated cell survival.

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