Division of Neurogenetics, Center for Neurological Diseases and Cancer, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
Department of Orthopaedic Surgery, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
Am J Sports Med. 2022 Apr;50(5):1317-1327. doi: 10.1177/03635465221077116. Epub 2022 Mar 2.
Wnt/β-catenin signaling suppresses the differentiation of cultured tenocytes, but its roles in tendon repair remain mostly elusive. No chemical compounds are currently available to treat tendon injury.
We hypothesized that the inhibition of Wnt/β-catenin signaling would accelerate tendon healing.
Controlled laboratory study.
Tendon-derived cells (TDCs) were isolated from rat Achilles tendons. The right Achilles tendon was injured via a dermal punch, while the left tendon was sham operated. A Wnt/β-catenin inhibitor, IWR-1, and an antihistamine agent, promethazine (PH), were locally and intramuscularly injected, respectively, for 2 weeks after surgery. The healing tendons were histologically and biomechanically evaluated.
The amount of β-catenin protein was increased in the injured tendons from postoperative weeks 0.5 to 2. Inhibition of Wnt/β-catenin signaling by IWR-1 in healing tendons improved the histological abnormalities and decreased β-catenin, but it compromised the biomechanical properties. As we previously reported that antihistamine agents suppressed Wnt/β-catenin signaling in human chondrosarcoma cells, we examined the effects of antihistamines on TDCs. We found that a first-generation antihistamine agent, PH, increased the expression of the tendon marker genes and in TDCs. Intramuscular injection of PH did not improve histological abnormalities, but it decreased β-catenin in healing tendons and increased the peak force and stiffness of the healing tendons on postoperative week 2. On postoperative week 8, however, the biomechanical properties of vehicle-treated tendons became similar to those of PH-treated tendons.
IWR-1 and PH suppressed Wnt/β-catenin signaling and improved the histological abnormalities of healing tendons. IWR-1, however, compromised the biomechanical properties of healing tendons, whereas PH improved them.
PH is a candidate repositioned drug that potentially accelerates tendon repair.
Wnt/β-连环蛋白信号抑制培养的腱细胞分化，但它在肌腱修复中的作用仍大多难以捉摸。目前尚无化学化合物可用于治疗肌腱损伤。
我们假设抑制 Wnt/β-连环蛋白信号会加速肌腱愈合。
对照实验室研究。
从大鼠跟腱中分离出肌腱源性细胞（TDC）。右侧跟腱通过皮打孔受伤，而左侧肌腱则假手术。手术后 2 周，分别局部和肌肉内注射 Wnt/β-连环蛋白抑制剂 IWR-1 和抗组胺药苯海拉明（PH）。对愈合的肌腱进行组织学和生物力学评估。
术后 0.5 至 2 周，受伤肌腱中的β-连环蛋白蛋白量增加。IWR-1 抑制愈合肌腱中的 Wnt/β-连环蛋白信号可改善组织学异常并降低β-连环蛋白，但会损害生物力学性能。由于我们之前报道过抗组胺剂可抑制人软骨肉瘤细胞中的 Wnt/β-连环蛋白信号，因此我们检查了抗组胺剂对 TDC 的影响。我们发现第一代抗组胺药苯海拉明（PH）可增加 TDC 中肌腱标记基因和的表达。肌肉内注射 PH 并不能改善组织学异常，但可降低愈合肌腱中的β-连环蛋白，并增加术后第 2 周愈合肌腱的峰值力和刚度。然而，术后第 8 周，载体处理的肌腱的生物力学性能变得类似于 PH 处理的肌腱。
IWR-1 和 PH 抑制了 Wnt/β-连环蛋白信号，并改善了愈合肌腱的组织学异常。然而，IWR-1 会损害愈合肌腱的生物力学性能，而 PH 则会改善其性能。
PH 是一种有潜力加速肌腱修复的重新定位药物。
