Effect of Metformin on Development of Tendinopathy Due to Mechanical Overloading in an Animal Model. (December 2020)

• Record Type: Journal Article
• Authors: Zhang, Jianying; Li, Feng; Nie, Daibang; Onishi, Kentaro; Hogan, MaCalus V.; Wang, James H-C.
• Is Part Of: Foot & ankle international. Volume 41:Number 12(2020)
• Page Start: 1455
• Page End: 1465
• Publication Date: 2020-12
• Subjects: mechanical overloading -- tendinopathy -- HMGB1 -- metformin; Foot -- Abnormalities -- Periodicals; Ankle -- Abnormalities -- Periodicals; Orthopedics -- Periodicals; 617.585
• DOI: 10.1177/1071100720966318
• Languages: English
• ISSNs: 1071-1007

Abstract

Background: Tendinopathy is a debilitating tendon disorder that affects millions of Americans and costs billions of health care dollars every year. High mobility group box 1 (HMGB1), a known tissue damage signaling molecule, has been identified as a mediator in the development of tendinopathy due to mechanical overloading of tendons in mice. Metformin (Met), a drug approved by the Food and Drug Administration used for the treatment of type 2 diabetes, specifically inhibits HMGB1. This study tested the hypothesis that Met would prevent mechanical overloading-induced tendinopathy in a mouse model of tendinopathy created by intensive treadmill running (ITR). Methods: C57BL/6J mice (female, 3 months old) were equally separated into 4 groups and treated for 24 weeks as follows: group 1 had cage control activities, group 2 received a single intraperitoneal injection of Met (50 mg/kg body weight) daily, group 3 underwent ITR to induce tendinopathy, and group 4 received daily Met injection along with ITR to inhibit HMGB1. Tendinopathic changes were assessed in Achilles tendons of all mice using histology, immunohistochemistry, and enzyme-linked immunosorbent assays. Results: ITR induced HMGB1 release into the tendon matrix and developed characteristics of tendinopathy as evidenced by the expression of macrophage marker CD68, proinflammatory molecules (COX-2, PGE2 ), cell morphological changes from normal elongated cells to round cells, high levels of expression of chondrogenic markers (SOX-9, collagen type II), and accumulation of proteoglycans in tendinopathic tendons. Daily injection of Met inhibited HMGB1 release and decreased these degenerative changes in ITR tendons. Conclusions: Inhibition of HMGB1 by injections of Met prevented tendinopathy development due to mechanical overloading in the Achilles tendon in mice. Clinical Relevance: Met may be able to be repurposed as a therapeutic option for preventing the development of tendinopathy in high-risk patients.