Journal of Orthopaedic Translation (Jan 2024)
Inhibition of PI3K/AKT signaling pathway prevents blood-induced heterotopic ossification of the injured tendon
- Xuri Chen,
- Yuwei Yang,
- Yuqing Gu,
- Junzhi Yi,
- Wenyu Yao,
- Zhuomin Sha,
- Hongwei Wu,
- Yunting Zhou,
- Zhonglin Wu,
- Fangyuan Bao,
- Jiasheng Wang,
- Ying Wang,
- Yuanhao Xie,
- Chenlu Gao,
- Boon Chin Heng,
- Hua Liu,
- Zi Yin,
- Xiao Chen,
- Jing Zhou,
- Hongwei Ouyang
Affiliations
- Xuri Chen
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 314400, China
- Yuwei Yang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 314400, China
- Yuqing Gu
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 314400, China
- Junzhi Yi
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 314400, China
- Wenyu Yao
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Zhuomin Sha
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Hongwei Wu
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 314400, China
- Yunting Zhou
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Zhonglin Wu
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 314400, China
- Fangyuan Bao
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 314400, China
- Jiasheng Wang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 314400, China
- Ying Wang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 314400, China
- Yuanhao Xie
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 314400, China
- Chenlu Gao
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Boon Chin Heng
- Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, 100081, China
- Hua Liu
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 314400, China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, 310058, China
- Zi Yin
- Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 314400, China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, 310058, China
- Xiao Chen
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 314400, China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, 310058, China
- Jing Zhou
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 314400, China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, 310058, China; Corresponding author. Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
- Hongwei Ouyang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 314400, China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, 310058, China; Corresponding author. Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
- Journal volume & issue
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Vol. 44
pp. 139 – 154
Abstract
Objective: 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. Methods: 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. Results: 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. Conclusion: 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.
