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

Autor:	Sakaguchi, Takefumi, Ohkawara, Bisei, Kishimoto, Yasuzumi, Miyamoto, Kentaro, Ishizuka, Shinya, Hiraiwa, Hideki, Ishiguro, Naoki, Imagama, Shiro, Ohno, Kinji
Předmět:	ACHILLES tendon injuries WOUND healing BIOLOGICAL models STATISTICS STAINS & staining (Microscopy) PROMETHAZINE ANIMAL experimentation ONE-way analysis of variance ANTIHISTAMINES SURGICAL complications CELLULAR signal transduction RATS INTRAMUSCULAR injections CYTOCHEMISTRY GENE expression T-test (Statistics) CHONDROSARCOMA DESCRIPTIVE statistics RESEARCH funding BIOMECHANICS CELL lines MOLECULAR structure POLYMERASE chain reaction DATA analysis DATA analysis software PHARMACODYNAMICS
Zdroj:	American Journal of Sports Medicine; Apr2022, Vol. 50 Issue 5, p1317-1327, 11p
Abstrakt:	Background: 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. Hypothesis: We hypothesized that the inhibition of Wnt/β-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/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. Results: 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 Mkx and Tnmd 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. Conclusion: 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. Clinical Relevance: PH is a candidate repositioned drug that potentially accelerates tendon repair. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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