Lei Lei, Wen Zhenkang, Zhang Xueyou, Zhang Haozhi, Luo Ying, Guo Jiaxin, Cao Mingde, Yao Hao, Fu Bruma Sai-Chuen, Tong Wenxue, Ling Samuel Ka-Kin, Wang Jiali, Qin Ling, Xu Jiankun, Yung Patrick Shu-Hang
Musculoskeletal Research Laboratory and Centre of Musculoskeletal Aging and Regeneration, Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; Disruptive Innovation Centre for Spatiotemporal Imaging, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China.
Musculoskeletal Research Laboratory and Centre of Musculoskeletal Aging and Regeneration, Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China.
Biomaterials. 2025 Jun 19;324:123507. doi: 10.1016/j.biomaterials.2025.123507.
Tendon injuries pose significant challenges in both athletes and the general population, often leading to prolonged healing, impaired functionality, and increased risk of re-injury. Current treatment options are limited and often yield unfavorable outcomes. Given that tendons are highly mechanosensitive tissues, recent studies highlight the crucial role of mechanotransduction in tissue repair. Piezo1, a mechanosensitive ion channel, has been recognized as a crucial factor attributing to many pathological processes in various tissues, but its specific role in tendon healing has not been previously explored. This study aimed to investigate the potential therapeutic benefits of GsMTx4-loaded GelMA on tendon regeneration and the prevention of heterotopic ossification following injury. Our findings indicate that following tendon injuries, Piezo1 expression was elevated. Activation of Piezo1 with Yoda1 suppressed osteogenic differentiation while promoting chondrogenic differentiation of tendon-derived stem cells. Treatment with GsMTx4 enhanced tendon healing and mitigated the formation of heterotopic ossification. RNA sequencing further implicated the Apelin signaling pathway in these processes, and inhibition of this pathway using ML221 significantly suppressed HO formation, suggesting a pivotal role for Apelin in tendon healing and ossification. Additionally, short-term immobilization was found to attenuate heterotopic ossification by modulating Piezo1 activity. Thus, inhibition of Piezo1 enhances tendon healing and reduces heterotopic ossification, potentially through the Apelin signaling pathway. These results underscore the critical role of Piezo1 in tendon biology and highlight the potential of targeting mechanosensitive ion channels, especially Piezo1, as a novel therapeutic approach for promoting tendon regeneration and preventing heterotopic ossification.
肌腱损伤给运动员和普通人群都带来了重大挑战，常常导致愈合时间延长、功能受损以及再次受伤风险增加。目前的治疗选择有限，且往往产生不理想的结果。鉴于肌腱是高度机械敏感组织，最近的研究强调了机械转导在组织修复中的关键作用。Piezo1是一种机械敏感离子通道，已被认为是多种组织中许多病理过程的关键因素，但其在肌腱愈合中的具体作用此前尚未被探索。本研究旨在探讨负载GsMTx4的GelMA对肌腱再生和损伤后预防异位骨化的潜在治疗益处。我们的研究结果表明，肌腱损伤后，Piezo1表达升高。用Yoda1激活Piezo1可抑制成骨分化，同时促进肌腱来源干细胞的软骨分化。用GsMTx4治疗可促进肌腱愈合并减轻异位骨化的形成。RNA测序进一步表明阿片肽信号通路参与了这些过程，使用ML221抑制该通路可显著抑制异位骨化的形成，表明阿片肽在肌腱愈合和骨化中起关键作用。此外，发现短期固定可通过调节Piezo1活性来减轻异位骨化。因此，抑制Piezo1可促进肌腱愈合并减少异位骨化，可能是通过阿片肽信号通路实现的。这些结果强调了Piezo1在肌腱生物学中的关键作用，并突出了靶向机械敏感离子通道，尤其是Piezo1，作为促进肌腱再生和预防异位骨化的新型治疗方法的潜力。
