Recovery of Tendon Injury by Targeting Its Root Cause and Enhancing Tendon Stem Cells
Abstract
Tendons are soft tissues that connect bone to muscle and as such have functions essential for ease of movement. Tendons are highly prone to injury by repetitive use or high force loads placed on them. Tendinopathy is a term for such injuries that exhibit painful conditions occurring consistently in and around tendon tissue with reduced flexibility and motion. Military personnel who undergo strenuous physical training and activity suffer from tendinopathy and most of them are at high risk for tendinopathy, thus reducing their duty time, and in some cases leading to disability and discharge. Overuse injuries, from military-related training and overuse, lead to nearly 70% of musculoskeletal (tendon, ligament, bones, muscles) injuries (MSIs). Between 2011 to 2016, approximately 70% of medical disability discharges in the Army were due to MSIs, and from 2010 to 2015 90% of disability discharges due to MSIs occurred within the Soldiers first year of service. In 2018, the direct patient care costs for combat-related MSIs in the Army was $434 million. The Achilles tendon is the largest tendon in the body but it is highly prone to injuries. Military Service Members with a history of Achilles tendon injury are three times more likely to develop subsequent tendinopathy. Moreover, a huge number (in excess of 18.2 million) of Veterans are over 65 years of age, raising the frequency of age-induced tendinopathy among them, considering the strenuous activity while at service, the chronic nature of the disease, and old age. Achilles tendinopathy is also common in athletic and occupational fronts due to tendon overuse, and also within the aging population due to a general declining function. Tendinopathy management is a huge socio-economic burden to both the military and general population that affects overall welfare and ability to work. Unfortunately, current treatment options such as RICE (rest, ice, compression, elevation) only offer temporary pain relief. Commonly prescribed pain medications and corticosteroid injections negatively affect the healing and repair of injured tendons. Moreover, such treatments pose risks that range from common side effects (nausea, vomiting, diarrhea, dizziness) to more serious effects such as stomach ulcers, bleeding, kidney, and liver failure. Therefore, there is an urgent need to develop a safe and effective treatment/prevention plan that treats the root cause of tendinopathy for military personnel to preserve the fighting force and enhance warfighting readiness and for the general population. We aim to develop a safe and effective therapy to prevent the development of Achilles tendinopathy and to treat existing Achilles tendinopathy in high-risk military personnel that can be translated to the high-risk general population as well. However, before this can be accomplished a preclinical study is necessary to assess our therapeutic approach in an animal model. We have developed a tendon overuse/tendinopathy animal model that simulates tendon overuse in humans. Using this model, we identified the root cause of tendinopathy as high mobility group box1 (HMGB1) that results in the development of tendinopathy. We developed strategies to inhibit HMGB1 using two well-known inhibitors and U.S. Food and Drug Administration-assessed compounds, glycyrrhizin (GL) and metformin (Met), that act in separate ways for HMGB1 inhibition. Our studies demonstrated that injection of GL and Met in our mouse model inhibits tendinopathy and hence pain. Furthermore, we have successfully formulated GL, Met, and their combination, GM, as topical lotions to prevent the negative actions of HMGB1. We have also shown that all three lotions penetrate the skin and reach the tendon in high enough concentrations to inhibit HMGB1 in mice. The focus of our study will be to assess GM lotion efficacy on tendon pain and inflammation, as well as to assess safety and potential side effects. Additionally, synergistic effec
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310617
Entities
People
- James Wang
Organizations
- United States Army