HMGB1 mediates the development of tendinopathy due to mechanical overloading

• Published in: PloS one Vol. 14; no. 9; p. e0222369
• Main Authors: Zhao, Guangyi, Zhang, Jianying, Nie, Daibang, Zhou, Yiqin, Li, Feng, Onishi, Kentaro, Billiar, Timothy, Wang, James H-C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.09.2019; Public Library of Science (PLoS)
• Subjects: Animals; Arthritis; Biology and Life Sciences; Blotting, Western; Care and treatment; Causes of; Chromosomal proteins; Collagen; Development and progression; Dinoprostone - metabolism; Enzyme-Linked Immunosorbent Assay; Exercise equipment; Extracellular matrix; Female; Gene expression; Glycyrrhizic Acid - pharmacology; Glycyrrhizin; HMGB1 protein; HMGB1 Protein - antagonists & inhibitors; HMGB1 Protein - metabolism; HMGB1 Protein - physiology; Immunology; Inflammation; Joint surgery; Laboratories; Matrix metalloproteinase; Matrix Metalloproteinase 3 - metabolism; Matrix metalloproteinases; Medicine; Medicine and Health Sciences; Metalloproteinase; Mice; Mice, Inbred C57BL; Overloading; Pain; Pathogenesis; Prostaglandin E2; Prostaglandins; Proteins; Rats, Sprague-Dawley; Research and Analysis Methods; Running; Sports medicine; Stromelysin 1; Surgery; Tendinitis; Tendinopathy - etiology; Tendinopathy - metabolism; Tendinopathy - physiopathology; Tendons; Tendons - cytology; Tendons - metabolism; Tendons - physiopathology; Treadmills; Weight-Bearing - physiology; Pittsburgh Pennsylvania; United States > US; China; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0222369

Mechanical overloading is a major cause of tendinopathy, but the underlying pathogenesis of tendinopathy is unclear. Here we report that high mobility group box1 (HMGB1) is released to the tendon extracellular matrix and initiates an inflammatory cascade in response to mechanical overloading in a mouse model. Moreover, administration of glycyrrhizin (GL), a naturally occurring triterpene and a specific inhibitor of HMGB1, inhibits the tendon's inflammatory reactions. Also, while prolonged mechanical overloading in the form of long-term intensive treadmill running induces Achilles tendinopathy in mice, administration of GL completely blocks the tendinopathy development. Additionally, mechanical overloading of tendon cells in vitro induces HMGB1 release to the extracellular milieu, thereby eliciting inflammatory and catabolic responses as marked by increased production of prostaglandin E2 (PGE2) and matrix metalloproteinase-3 (MMP-3) in tendon cells. Application of GL abolishes the cellular inflammatory/catabolic responses. Collectively, these findings point to HMGB1 as a key molecule that is responsible for the induction of tendinopathy due to mechanical overloading placed on the tendon.