Deletion of NFKB1 enhances canonical NF-κB signaling and increases macrophage and myofibroblast content during tendon healing

• Published in: Scientific reports 2019-07, Vol.9 (1), p.10926-11, Article 10926
• Main Authors: Best, Katherine T., Lee, Fredella K., Knapp, Emma, Awad, Hani A., Loiselle, Alayna E.
• Format: Article
• Language: English
• Subjects: 13/51; 631/337; 631/80; 96/95; Actins - metabolism; Animals; Biomechanics; Calcium-Binding Proteins - metabolism; Cell activation; Chemokine CCL2 - metabolism; Collagen; Collagen (type I); Collagen - metabolism; Gene Deletion; Gliding; Humanities and Social Sciences; Kinases; Macrophages; Macrophages - metabolism; MAP kinase; Mechanical properties; Mice; Molecular modelling; Monocyte chemoattractant protein 1; multidisciplinary; Myofibroblasts - metabolism; NF-kappa B p50 Subunit - genetics; NF-kappa B p50 Subunit - metabolism; NF-κB protein; Protein kinase; Receptors, G-Protein-Coupled - metabolism; Repressors; Science; Science (multidisciplinary); Signal Transduction; Tendon Injuries - metabolism; Tendons; Tendons - cytology; Tendons - metabolism; Tumor necrosis factor; Tumor Necrosis Factor-alpha - metabolism; Wound Healing
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-47461-5

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.