Inhibition of PI3K/AKT signaling pathway prevents blood-induced heterotopic ossification of the injured tendon

• Published in: Journal of orthopaedic translation Vol. 44; pp. 139 - 154
• Main Authors: Xuri Chen, Yang, Yuwei, Gu, Yuqing, Yi, Junzhi, Yao, Wenyu, Sha, Zhuomin, Wu, Hongwei, Zhou, Yunting, Wu, Zhonglin, Bao, Fangyuan, Wang, Jiasheng, Wang, Ying, Xie, Yuanhao, Gao, Chenlu, Heng, Boon Chin, Liu, Hua, Yin, Zi, Chen, Xiao, Zhou, Jing, Ouyang, Hongwei
• Format: Journal Article
• Language: English
• Published: Singapore Elsevier B.V 01.01.2024; Chinese Speaking Orthopaedic Society; Elsevier
• Subjects: Blood; Heterotopic ossification; Inflammation; Original; PI3K/AKT signaling pathway; Tendon stem/progenitor cells; Heterotopic ossification; Inflammation; Tendon stem/progenitor cells; PI3K/AKT signaling pathway; Blood
• ISSN: 2214-031X; 2214-0328
• DOI: 10.1016/j.jot.2023.11.003

It is a common clinical phenomenon that blood infiltrates into the injured tendon caused by sports injuries, accidental injuries, and surgery. However, the role of blood infiltration into the injured tendon has not been investigated. A blood-induced rat model was established and the impact of blood infiltration on inflammation and HO of the injured tendon was assessed. Cell adhesion, viability, apoptosis, and gene expression were measured to evaluate the effect of blood treatment on tendon stem/progenitor cells (TSPCs). Then RNA-seq was used to assess transcriptomic changes in tendons in a blood infiltration environment. At last, the small molecule drug PI3K inhibitor LY294002 was used for in vivo and in vitro HO treatment. Blood caused acute inflammation in the short term and more severe HO in the long term. Then we found that blood treatment increased cell apoptosis and decreased cell adhesion and tenonic gene expression of TSPCs. Furthermore, blood treatment promoted osteochondrogenic differentiation of TSPCs. Next, we used RNA-seq to find that the PI3K/AKT signaling pathway was activated in blood-treated tendon tissues. By inhibiting PI3K with a small molecule drug LY294002, the expression of osteochondrogenic genes was markedly downregulated while the expression of tenonic genes was significantly upregulated. At last, we also found that LY294002 treatment significantly reduced the tendon HO in the rat blood-induced model. Our findings indicate that the upregulated PI3K/AKT signaling pathway is implicated in the aggravation of tendon HO. Therefore, inhibitors targeting the PI3K/AKT pathway would be a promising approach to treat blood-induced tendon HO. Schematic diagram of the role of the blood on the heterotopic ossification of the injured tendon. [Display omitted]