Rapamycin-mediated inhibition of the mTOR pathway promotes tendon healing in a collagenase-induced Achilles tendinopathy

Sep 29, 2026

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Achilles tendinopathy is a prevalent musculoskeletal disorder driven by overuse and repetitive injury, causing collagen micro-damage and impaired structural repair. This study tested whether rapamycin, an mTOR pathway inhibitor, improves tendon healing in a collagenase-induced Achilles tendinopathy model. Collagenase injection followed by intraperitoneal rapamycin was assessed with histology, immunohistochemistry, Western blot, and biomechanical testing, showing reduced mTOR signaling and improved tissue recovery.

LanguageEnglish

CategoryHealthcare

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Pages11

Reading Time28 min

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Abstract

Background

Objective

Methods

Results

Conclusion

Introduction

Zhang et al. Journal of Orthopaedic Surgery and Research (2026) 21:5 [https://doi.org/10.1186/s13018-025-06524-2](https://doi.org/10.1186/s13018-025-06524-2) Journal of Orthopaedic Surgery and Research RESEARCH Open Access Rapamycin-mediated inhibition of the mTOR pathway promotes tendon healing in a collagenase-induced achilles tendinopathy Eryang Zhang 1†, Xin Wang2†, Zhikang Zhou 1 and Chen Zhang3* Abstract Background Achilles tendinopathy is a common musculoskeletal disorder, typically caused by overuse and repetitive injury, leading to micro-damage and structural alterations of collagen fibers. Traditional treatment methods have limited efficacy. The mammalian target of rapamycin (mTOR) pathway, a crucial regulator of tissue repair, has emerged as a potential therapeutic target for tendinopathy. Objective This study aimed to evaluate the impact of the mTOR pathway inhibitor, rapamycin, on tendon healing ina collagenase-induced Achilles tendinopathy model (CITM) . Methods Tendinopathy was induced by collagenase injection into the Achilles tendon, followed by an intraperitoneal injection of rapamycin. Tendon tissues were collected at various time points for histological, immunohistochemical, Western blot, and biomechanical analyses. Results Histological and immunohistochemical analyses revealed that the collagenase injection induced tendon damage. At 4-and 8-week post-injection, there was a significant upregulation in the expression of the cartilage markers Col-2 and SOX-9 . Rapamycin treatment resulted in a marked reduction in cellular density and significantly improved histological scores while inhibiting Col-2 and SOX-9 expression. Western blot indicated that rapamycin effectively suppressed the mTOR signaling pathway activated by collagenase, reducing the phosphorylation levels of mTOR, AKT, and p70/S6K. Finally, biomechanical testing revealed that the diameter of the Achilles tendon normalized after rapamycin treatment, but non-significant differences in maximum mechanical load, tensile stress, or elastic modulus were observed compared to the CITM group. Conclusion Rapamycin effectively promotes Achilles tendon healing by inhibiting the collagenase-activated mTOR signaling pathway, particularly exhibiting potential in mitigating cartilage formation and improving histological recovery. Although its impact on biomechanical strength is limited, it may serve as a promising new strategy for treating tendinopathy. Keywords Achilles tendinopathy, mTOR signaling pathway, Rapamycin, Tendon healing, Collagenase-induced tendon injury †Eryang Zhang and Xin Wang have contributed equally to this work. *Correspondence: Chen Zhang [18535999678@163.com](18535999678@163.com) 1Department of Orthopedics, The Affiliated Yuncheng Central Hospital of Shanxi Medical University, Yuncheng, Shanxi, China 2Lintong Rehabilitation and Convalescent Centre, PLA Joint Logistics Support Force, Xi’an, Shaanxi, China 3Department of Orthopaedics, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain p

FAQs

What problem does the study address in Achilles tendinopathy?

Achilles tendinopathy causes persistent pain and impaired recovery due to collagen micro-damage and structural alterations, and existing treatments show limited long-term efficacy. The study targets the mTOR pathway as a therapeutic opportunity.

How was rapamycin administered and how was tendon healing evaluated?

Tendinopathy was induced by collagenase injection into the Achilles tendon, followed by intraperitoneal rapamycin. Healing was assessed using histological and immunohistochemical analyses, Western blot, and biomechanical testing at multiple time points.

What mechanisms did rapamycin affect according to the results?

Rapamycin reduced cellular density, improved histological scores, and inhibited cartilage-related markers Col-2 and SOX-9. Western blot showed suppression of collagenase-activated mTOR signaling, including decreased phosphorylation of mTOR, AKT, and p70/S6K.

Sep 29, 2026

Uploaded by Mimi