Dysregulation of Wingless and Int-1 (Wnt) signaling has been strongly associated with development and progression of osteoarthritis (OA). Here, we set out to investigate the independent effects of... Show moreDysregulation of Wingless and Int-1 (Wnt) signaling has been strongly associated with development and progression of osteoarthritis (OA). Here, we set out to investigate the independent effects of either mechanical stress (MS) or inflammation on Wnt signaling in human neocartilage pellets, and to relate this Wnt signaling to OA pathophysiology. OA synovium-conditioned media (OAS-CM) was collected after incubating synovium from human end-stage OA joints for 24 h in medium. Cytokine levels in the OAS-CM were determined with a multiplex immunoassay (Luminex). Human neocartilage pellets were exposed to 20% MS, 2% OAS-CM or 1 ng/mL Interleukin-1 & beta; (IL-1 & beta;). Effects on expression levels of Wnt signaling members were determined by reverse transcription-quantitative polymerase chain reaction. Additionally, the expression of these members in articular cartilage from human OA joints was analyzed in association with joint space narrowing (JSN) and osteophyte scores. Protein levels of IL-1 & beta;, IL-6, IL-8, IL-10, tumor necrosis factor & alpha;, and granulocyte-macrophage colony-stimulating factor positively correlated with each other. MS increased noncanonical WNT5A and FOS expression. In contrast, these genes were downregulated upon stimulation with OAS-CM or IL-1 & beta;. Furthermore, Wnt inhibitors DKK1 and FRZB decreased in response to OAS-CM or IL-1 & beta; exposure. Finally, expression of WNT5A in OA articular cartilage was associated with increased JSN scores, but not osteophyte scores. Our results demonstrate that MS and inflammatory stimuli have opposite effects on canonical and noncanonical Wnt signaling in human neocartilage. Considering the extent to which MS and inflammation contribute to OA in individual patients, we hypothesize that targeting specific Wnt pathways offers a more effective, individualized approach. Show less
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... Show moreThere 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 disk, and 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 histopathologic 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 disulfide 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. Show less
