The potential roles of high mobility group box 1 (HMGB1) in musculoskeletal disease: a systematic review.

There is increasing evidence for the involvement of high mobility group box 1 (HMGB1) in inflammation, angiogenesis, and tumorigenesis. However, no studies have reviewed the role of HMGB1 in musculoskeletal disease. This systematic review aimed to evaluate the literature regarding the potential roles of HMGB1 in musculoskeletal disease (joint, tendon, ligament, intervertebral disc, bone). After searching PubMed, MEDLINE, and EMBASE databases up to 01‐01‐2020, 66 articles that measured HMGB1 expression in musculoskeletal disease were included. Immune and tissue resident stromal cells expressed HMGB1, and both diseased human tissues and animal disease models showed increased HMGB1 expression relative to controls. Administration of recombinant HMGB1 to diseased musculoskeletal tissues induced inflammation, whereas blocking HMGB1 ameliorated histopathological and clinical severity of disease. HMGB1 redox status was investigated in only 3% of the articles: fully reduced HMGB1 promoted chemotaxis of leukocytes and tissue repair, whereas disulphide HMGB1 acted as a pro‐inflammatory mediator. Our review highlights that while HMGB1 is an important mediator in musculoskeletal disease, its redox status remains understudied. Identification of HMGB1 redox status in musculoskeletal tissues is critical to advance understanding of the diverse biological functions of HMGB1 in musculoskeletal disease. Importantly, this will inform future therapeutic strategies to target HMGB1.