Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14642, United States of America.
Department of Biomedical Engineering, University of Rochester, Rochester, New York, United States of America.
Sci Rep. 2019 Jul 29;9(1):10926. 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.
屈肌腱损伤后会形成过多的疤痕组织，限制运动范围并增加再次断裂的发生率。目前尚未明确控制肌腱愈合的分子机制。经典的核因子 kappa B（NF-κB）和丝裂原活化蛋白激酶（MAPK）通路都与肌腱愈合有关。基因 NFKB1（蛋白 p105/p50）参与 NF-κB 和 MAPK 信号转导通路。本研究假设 NFKB1 缺失会通过信号抑制因子的丧失增加 NF-κB 和 MAPK 的激活，从而导致基质沉积增加和生物力学特性改变。与假设一致，NFKB1 缺失增加了 NF-κB 和 MAPK 信号的激活。虽然滑动功能不受影响，但 NFKB1 缺失导致肌腱在修复后 4 周时明显变硬，且强度增加趋势。NFKB1 缺失导致胶原蛋白沉积增加、巨噬细胞募集增加和肌成纤维细胞增多。此外，NFKB1 缺失增加了基质相关基因（Col1a1、Col3a1）、巨噬细胞相关基因（Adgre1、Ccl2）、肌成纤维细胞标志物（Acta2）和一般炎症（Tnf）的表达。综上所述，这些数据表明，NFKB1 缺失通过增加 NF-κB 和 MAPK 的激活，增加修复处的巨噬细胞和肌成纤维细胞含量，从而促进胶原蛋白沉积和生物力学特性的改变。
