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

Huaji Jiang Yan Ding Yongfu Wu Yingchao Xie Qinyu Tian Cheng Yang Yakui Liu Xuemei Lin Bin Song Hebei He Li Wan Xinggui Tian

Phytomedicine

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:

Published: December 2024

- This study explores how eupalinolide A (EA) can prevent abnormal bone formation in tendon-derived stem cells (TDSCs), which is important for treating traumatic heterotopic ossification (HO).
- EA was found to inhibit the osteogenic differentiation of TDSCs by targeting the YAP signaling pathway, promoting YAP's degradation through a specific autophagy pathway.
- In mouse models, local injections of EA successfully reduced tendon HO following trauma, highlighting its potential as a therapeutic agent and suggesting that targeting HECW1 involved in YAP degradation could be a new treatment strategy.

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.

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http://dx.doi.org/10.1016/j.phymed.2024.156163	DOI Listing

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