Abstract
Flexor tendon injuries heal with excessive scar tissue that limits range of motion and increases incidence of re-rupture. The molecular mechanisms that govern tendon healing are not well defined. Both the canonical nuclear factor kappa B (NF-κB) and mitogen activated protein kinase (MAPK) pathways have been implicated in tendon healing. The gene NFKB1 (proteins p105/p50) is involved in both NF-κB and MAPK signaling cascades. In the present study, we tested the hypothesis that global NFKB1 deletion would increase activation of both NF-κB and MAPK through loss of signaling repressors, resulting in increased matrix deposition and altered biomechanical properties. As hypothesized, NFKB1 deletion increased activation of both NF-κB and MAPK signaling. While gliding function was not affected, NFKB1 deletion resulted in tendons that were significantly stiffer and trending towards increased strength by four weeks post-repair. NFKB1 deletion resulted in increased collagen deposition, increase macrophage recruitment, and increased presence of myofibroblasts. Furthermore, NFKB1 deletion increased expression of matrix-related genes (Col1a1, Col3a1), macrophage-associated genes (Adgre1, Ccl2), myofibroblast markers (Acta2), and general inflammation (Tnf). Taken together, these data suggest that increased activation of NF-κB and MAPK via NFKB1 deletion enhance macrophage and myofibroblast content at the repair, driving increased collagen deposition and biomechanical properties.
Highlights
Tendons are a dense connective tissue primarily composed of type I collagen
At day 14 post-repair, there were no apparent differences in p-ERK1/2 between genotypes, which suggests NFKB1-independent activation of ERK1/2 signaling at this time point (Fig. 2D)
While no statistically significant differences in mechanical properties were observed between NFKB1 wildtype (NFKB1WT) and NFKB1KO repairs at 14 days post-repair, the maximum load at failure was reduced in NFKB1KO relative to NFKB1HET at D14
Summary
Tendons are a dense connective tissue primarily composed of type I collagen. The collagen fibrils are organized into a hierarchical structure that confers strength and enables the tendon to transmit forces from muscle to bone. Evaluation of repaired tendons identified changes in the cellular environment, matrix deposition, and downstream gene targets of NF-κB and MAPK signaling, which may drive the mechanical phenotypes that were observed during healing. These data provide evidence that increased activation of canonical NF-κB and ERK1/2 signaling, likely resulting from loss of p50 repressors and freeing of the TPL2 kinase, synergistically result in increased extracellular matrix deposition at the injury site, potentially driven by an increased presence of macrophages and myofibroblasts
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