Ingenium 2020
Metformin administration impairs tendon wound healing Catherine Grace P. Hobayan , Arthur R. McDowella, Feng Lia, Jianying Zhanga*, and James H-C. Wanga, b, c a, b
MechanoBiology Laboratory, Departments of Orthopaedic Surgery, Bioengineering, cPhysical Medicine and Rehabilitation, University of Pittsburgh, PA, USA
a
b
Grace Hobayan is a fourth-year bioengineering student at the University of Pittsburgh Swanson School of Engineering. She is interested in the intersection between cellular/tissue engineering and biomechanics, and she plans to attend medical school after graduation and apply Grace Hobayan her bioengineering background to the practice of medicine. Currently, she serves as a Teaching Assistant for Intramural Internship (BIOENG 1002), where she helps bioengineering students develop presentations and effectively communicate about their research projects to a wide variety of audiences. Dr. Jianying Zhang has interdisciplinary education background and overlapping research interests. Dr. Zhang’s research has resulted in over one hundred peerreviewed research publications and more than 35 patents, and some of the products generated from her patents have been Dr. Jianying Zhang approved by the FDA (USA) and put into clinical practice. Currently, Dr. Zhang is a research associate professor in the Department of Orthopaedic Surgery at the University of Pittsburgh School of Medicine.
Significance Statement
Obese patients with Type II diabetes often experience tendon injuries due to the exertion of higher loads on their tendons. Metformin is one of the most common medications for such prescribed for Type II diabetes. However, the effect of metformin on tendon disorders is largely unknown. This study has shown that HMGB1 is necessary for tendon healing, and the inhibition of HMGB1 by metformin impairs tendon wound healing. Thus, metformin may exacerbate healing of injured tendons in obese diabetic patients.
Category: Experimental research
Keywords: Metformin, HMGB1, cell tracking, tendinopathy Abbreviations: HMGB1 - High mobility group box 1, Scx- Scleraxis, α-SMA - α-smooth muscle actin, Met - metformin, PT - Patellar tendon, AT - Achilles tendon, TSC - tendon stem cell
Abstract
Tendon injury is common, and injured tendons have a limited healing ability. High mobility group box-1 (HMGB1) has been found to enhance wound healing by recruiting cells to migrate to the wound area and increasing cell proliferation. However, the role of HMGB1 in tendon wound healing is currently unknown. Metformin, a hypoglycemic anti-inflammatory drug for Type II diabetes, inhibits HMGB1 activity by binding to its C-tail. Therefore, in this pilot study, we hypothesized that inhibiting HMGB1 by metformin slows the healing of wounded tendons due to its inhibition of HMGB1 activity. To test this hypothesis, a window defect was created in the patellar tendon and Achilles tendon of α-SMA-Ai9-Scx-GFP transgenic mice. The animals were injected either with saline every day (control group), or five days metformin before surgery (short term metformin), or metformin every day (long term metformin). Fluorescence microscopy images of tendon sections taken 4 weeks post-injury indicated that paratenon cells migrated into the wounded area of the tendon in the saline injection mice (control group), but not in the groups that received metformin injection. Cell densities in the wound area and HMGB1 serum levels were higher in the absence of metformin. This may indicate that metformin inhibited HMGB1 activity and reduced wound healing by blocking the recruitment and migration of paratenon cells to the wounded area. Thus, metformin administration limits the healing capacity for wounded Achilles tendons by limiting the migration of paratenon cells to wounded areas.
1. Introduction
Tendinopathy is a prevalent tendon disorder that affects a large proportion of people in both athletic and occupational settings [1]. However, the current treatment options for tendinopathy are largely palliative because the mechanisms causing the tendon disorder are not well understood [2]. Many intrinsic and extrinsic risk/causative factors can predispose to the development of tendinopathy. Among them, diabetes mellitus is an important risk/ causative factor [3]. Obese patients with Type II diabetes often experience tendinopathy due to the exertion of higher loads on their tendons. Metformin is a hypoglycemic anti-inflammatory drug commonly used for treatment of Type II diabetes. High mobility group box 1 (HMGB1) is an alarmin protein released from necrotic cells to induce inflammatory responses in the human body. Extracellular HMGB1 induces several responses, including the activation of proinflammatory cytokines, cell proliferation and stromal cell matrix responses [4]. Metformin has been shown to bind to the acidic tail of HMGB1 and inhibit its inflammatory activity in a concentration-dependent manner [5]. The inflammatory activity of HMGB1 has also been shown to contribute to tendon injury mechanisms by regulating inflammatory cytokines and matrix changes [6]. No prior studies have analyzed the effects of metformin in the context of tendinopathy.
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