2. Academic Validation
  3. Eupalinolide A attenuates trauma-induced heterotopic ossification of tendon in mice by promoting YAP degradation through TOLLIP-mediated selective autophagy

Eupalinolide A attenuates trauma-induced heterotopic ossification of tendon in mice by promoting YAP degradation through TOLLIP-mediated selective autophagy

  • Phytomedicine. 2024 Dec:135:156163. doi: 10.1016/j.phymed.2024.156163.
Huaji Jiang 1,  Yan Ding 2,  Yongfu Wu 3,  Yingchao Xie 4,  Qinyu Tian 5,  Cheng Yang 6,  Yakui Liu 7,  Xuemei Lin 8,  Bin Song 9,  Hebei He 10,  Li Wan 11,  Xinggui Tian 12
Affiliations

Affiliations

  • 1 Department of Orthopaedics, The State Key Clinical Specialty in Orthopaedics, Yuebei People's Hospital Affiliated to Shantou University Medical College, Shaoguan, Guangdong, China.
  • 2 Department of Diagnostics, School of Medicine, Hunan University of Medicine, Huaihua 418000 Hunan Province, China.
  • 3 Department of Pharmacy, Yuebei People's Hospital Affiliated to Shantou University Medical College, Shaoguan, Guangdong, China.
  • 4 Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
  • 5 Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 6 Department of Urology, The Third Affiliated Hospital of Southern Medical University, No. 183 West Zhongshan Road, Tianhe District, 510630 Guangzhou, China.
  • 7 Center for Translational Bone, Joint and Soft Tissue Research, University Hospital Carl Gustav Carus at TUD Dresden University of Technology, Fetscherstraße 74, 01307, Dresden, Germany.
  • 8 Department of Pediatric Orthopedics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510515, China.
  • 9 Department of Joint Surgery and Sports Medicine, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510655, China. Electronic address: songbin3@mail.sysu.edu.cn.
  • 10 Department of Sports Medicine, The First Affiliated Hospital, Guangdong Provincial Key Laboratory of Speed Capability, The Guangzhou Key Laboratory of Precision Orthopedics and Regenerative Medicine, Jinan University, 510630, Guangzhou, China. Electronic address: beihehe889@163.com.
  • 11 Department of Pain Medicine, The State Key Clinical Specialty in Pain Medicine, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China. Electronic address: wanli5000cn@163.com.
  • 12 Center for Translational Bone, Joint and Soft Tissue Research, University Hospital Carl Gustav Carus at TUD Dresden University of Technology, Fetscherstraße 74, 01307, Dresden, Germany; University Center of Orthopaedic, Trauma and Plastic Surgery, University Hospital Carl Gustav Carus at TUD Dresden University of Technology, Dresden, Germany. Electronic address: tian_xinggui@163.com.
PMID: 39467430 DOI: 10.1016/j.phymed.2024.156163
Abstract

Background: Inhibiting the aberrant osteogenic differentiation of tendon-derived stem cells (TDSCs) is an effective strategy for treating traumatic heterotopic ossification (HO) in tendons.

Purpose: This study aimed to investigate whether eupalinolide A (EA) could prevent tendon HO progression by suppressing the osteogenic differentiation of TDSCs.

Methods: The effects of EA on osteogenic differentiation and key signaling pathways in TDSCs were examined in vitro to assess its therapeutic potential and elucidate the underlying molecular mechanisms. Furthermore, the therapeutic efficacy of EA was evaluated in a mouse model of trauma-induced tendon HO via local injection therapy.

Results: EA significantly inhibited the osteogenic differentiation of TDSCs by targeting YAP in vitro. Specifically, EA facilitated the recruitment of E3 ubiquitin Ligase HECW1, which mediated K27-linked polyubiquitination of YAP, leading to its degradation via the TOLLIP-mediated selective Autophagy pathway. In vivo, EA mitigated trauma-induced tendon HO by inhibiting the YAP pathway.

Conclusions: EA could be a potential therapeutic agent for treating traumatic tendon HO. The therapeutic target HECW1 involved in YAP degradation via Autophagy presents a new therapeutic avenue to attenuate the progression of traumatic tendon HO.

Keywords

Autophagy; Eupalinolide A; Heterotopic ossification; Tendon; Ubiquitination; YAP.

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