Promethazine Downregulates Wnt/beta-Catenin Signaling and Increases the Biomechanical Forces of the Injured Achilles Tendon in the Early Stage of Healing

Background: Wnt/beta-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. Hypothesis: We hypothesized that the inhibition of Wnt/beta-catenin signaling would accelerate tendon healing. Study Design: Controlled laboratory study. Methods: 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/beta-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. Results: The amount of beta-catenin protein was increased in the injured tendons from postoperative weeks 0.5 to 2. Inhibition of Wnt/beta-catenin signaling by IWR-1 in healing tendons improved the histological abnormalities and decreased beta-catenin, but it compromised the biomechanical properties. As we previously reported that antihistamine agents suppressed Wnt/beta-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 Mkx and Tnmd in TDCs. Intramuscular injection of PH did not improve histological abnormalities, but it decreased beta-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. Conclusion: IWR-1 and PH suppressed Wnt/beta-catenin signaling and improved the histological abnormalities of healing tendons. IWR-1, however, compromised the biomechanical properties of healing tendons, whereas PH improved them.