{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:20:00Z","timestamp":1792034400732,"version":"4.4.0"},"reference-count":38,"publisher":"SAGE Publications","issue":"12","license":[{"start":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T00:00:00Z","timestamp":1605139200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/100005440","name":"Center for Scientific Review","doi-asserted-by":"publisher","award":["AR061395"],"award-info":[{"award-number":["AR061395"]}],"id":[{"id":"10.13039\/100005440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005440","name":"Center for Scientific Review","doi-asserted-by":"publisher","award":["AR065949"],"award-info":[{"award-number":["AR065949"]}],"id":[{"id":"10.13039\/100005440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005440","name":"Center for Scientific Review","doi-asserted-by":"publisher","award":["AR070340"],"award-info":[{"award-number":["AR070340"]}],"id":[{"id":"10.13039\/100005440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Foot Ankle Int."],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      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, PGE\n                      <jats:sub>2<\/jats:sub>\n                      ), 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Inhibition of HMGB1 by injections of Met prevented tendinopathy development due to mechanical overloading in the Achilles tendon in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Relevance:<\/jats:title>\n                    <jats:p>Met may be able to be repurposed as a therapeutic option for preventing the development of tendinopathy in high-risk patients.<\/jats:p>\n                  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