Zhao, Guangyi
(2017)
HMGB1 INDUCES TENDINOPATHY DEVELOPMENT DUE TO MECHANICAL OVERLOADING.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
Tendon is a band of connective tissue that transmits muscular forces to the bone, and as a result, is constantly subjected to large mechanical loads. Over 10 million people suffer from tendon injury and/or chronic tendinopathy in the United States with the cost of treatment exceeding 30 billion dollars each year. While mechanical overloading is considered to be a major risk factor, the molecular mechanism for the development of tendinopathy is largely unknown. The highly conserved nuclear protein, high mobility group box1 (HMGB1), is identified as a potent inflammatory mediator when released to the extracellular matrix from inflammatory or stromal cells in response to stimulation with inflammatory agents or mechanical stress.
Therefore, in this study we hypothesized that HMGB1 is responsible for tendinopathy development due to mechanical overloading placed on the tendon. To test the hypothesis, we performed in vitro and in vivo studies. We found that HMGB1 in tendon cells translocates from nucleus to extracellular matrix when challenged with mechanical overloading in vitro and in vivo. When implanted in rat patellar tendons in vivo, HMGB1 causes cellular and structural changes that mimic the features of tendinopathy. Treatment with glycyrrhizin (GL), a specific inhibitor of HMGB1, blocks HMGB1-induced inflammatory reaction in vitro and mechanical overloading-induced tendon inflammation in vivo. GL treatment also largely reduces degenerative changes in Achilles tendons of mice subjected to chronic mechanical overloading through treadmill running.
Thus, our study shows that extracellular HMGB1 is a key molecule that plays a vital role in the onset of tendon inflammation, and eventual tendon degeneration in response to mechanical overloading. The findings of this study also indicate that GL may be used to prevent tendinopathy development by blocking HMGB1 signaling in the tendon, particularly in the athletic setting.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
26 September 2017 |
| Date Type: |
Publication |
| Defense Date: |
26 April 2017 |
| Approval Date: |
26 September 2017 |
| Submission Date: |
15 May 2017 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
208 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
HMGB1, tendon, tendinopathy, mechanical overloading, inflammation |
| Date Deposited: |
26 Sep 2018 05:00 |
| Last Modified: |
26 Sep 2018 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/32783 |
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HMGB1 INDUCES TENDINOPATHY DEVELOPMENT DUE TO MECHANICAL OVERLOADING. (deposited 26 Sep 2018 05:00)
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