Mechanical overload-induced release of extracellular mitochondrial particles from tendon cells leads to inflammation in tendinopathy

• Published in: Experimental & molecular medicine Vol. 56; no. 3; pp. 583 - 599
• Main Authors: Chen, Ziming, Li, Mengyuan, Chen, Peilin, Tai, Andrew, Li, Jiayue, Bassonga, Euphemie Landao, Gao, Junjie, Liu, Delin, Wood, David, Kennedy, Brendan F., Zheng, Qiujian, Zheng, Ming H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2024; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 13; 13/107; 14; 14/19; 14/34; 14/63; 38; 38/77; 38/91; 631/80/642/333/1465; 692/308/1426; 692/420/256/2515; 692/699/578; 82; 82/29; 96/21; Acetylcysteine; Artificial intelligence; Biomedical and Life Sciences; Biomedicine; Bioreactors; Chemotaxis; Confocal microscopy; Inflammation; Macrophages; Mechanical loading; Medical Biochemistry; Microenvironments; Mitochondria; Molecular Medicine; Muscles; Musculoskeletal diseases; Stem Cells; Tendons; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-024-01183-5

Tendinopathy is one of the most common musculoskeletal diseases, and mechanical overload is considered its primary cause. However, the underlying mechanism through which mechanical overload induces tendinopathy has not been determined. In this study, we identified for the first time that tendon cells can release extracellular mitochondria (ExtraMito) particles, a subtype of medium extracellular particles (mEPs), into the environment through a process regulated by mechanical loading. RNA sequencing systematically revealed that oxygen-related reactions, extracellular particles, and inflammation were present in diseased human tendons, suggesting that these factors play a role in the pathogenesis of tendinopathy. We simulated the disease condition by imposing a 9% strain overload on three-dimensional mouse tendon constructs in our cyclic uniaxial stretching bioreactor. The three-dimensional mouse tendon constructs under normal loading with 6% strain exhibited an extended mitochondrial network, as observed through live-cell confocal laser scanning microscopy. In contrast, mechanical overload led to a fragmented mitochondrial network. Our microscopic and immunoblot results demonstrated that mechanical loading induced tendon cells to release ExtraMito particles. Furthermore, we showed that mEPs released from tendon cells overloaded with a 9% strain (mEP 9% ) induced macrophage chemotaxis and increased the production of proinflammatory cytokines, including IL-6, CXCL1, and IL-18, from macrophages compared to mEP 0% , mEP 3% , and mEP 6% . Partial depletion of the ExtraMito particles from mEP 9% by magnetic-activated cell sorting significantly reduced macrophage chemotaxis. N-acetyl-L-cysteine treatment preserved the mitochondrial network in overloaded tendon cells, diminishing overload-induced macrophage chemotaxis toward mEP 9% . These findings revealed a novel mechanism of tendinopathy; in an overloaded environment, ExtraMito particles convey mechanical response signals from tendon cells to the immune microenvironment, culminating in tendinopathy. Mechanical overload unveils new culprit in tendinopathy: extracellular mitochondria Tendons, essential tissues linking muscles to bones, can deteriorate due to repeated stress, causing tendinopathy—a painful condition affecting many. Despite usual treatments like painkillers and physical therapy, there’s a shortage of therapies addressing the primary causes of tendinopathy. They gathered tendon samples from patients, conducted RNA sequencing, and used a three-dimensional bioreactor to mimic tendon stress. This research, involving Minghao Zheng, aimed to bridge this knowledge gap by studying the cellular reactions at the molecular level in human tendons affected by tendinopathy. They discovered that stressed tendons release particles containing mitochondria, which then affect immune cells and can cause inflammation—a primary factor in tendinopathy. The study showed stressed tendons release particles that can initiate inflammation, suggesting a new understanding of the fundamental mechanisms of tendinopathy. The results could lead to innovative treatments targeting these cellular processes. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.