STAT3 phosphorylation inhibition for treating inflammation and new bone formation in ankylosing spondylitis

Objective. AS is a rheumatic disease characterized by chronic inflammation and bony ankylosis. This study was to evaluate whether a signal transducer and activator of transcription 3 phosphorylation inhibitor (stat3-p lnh) could treat both chronic inflammation and bone formation in AS. Methods. Primary AS osteoprogenitor cells and spinal entheseal cells were examined for osteogenic differentiation. SF mononuclear cells (SFMCs) and lamina propria mononuclear cells (LPMCs) were obtained from AS patients. Inflammatory cytokine-producing cells were analysed using flow cytometry and ELISA. Female SKG mice were treated with stat3-p lnh, IL-17A blocker or vehicle. Inflammation and new bone formation were evaluated using immunohistochemistry, PET and micro-CT. Results. In the SKG mouse model, stat3-p lnh significantly suppressed arthritis, enthesitis, spondylitis and ileitis. In experiments culturing SFMCs and LPMCs, the frequencies of IFN-gamma-, IL-17A- and TNF-alpha-producing cells were significantly decreased after stat3-p lnh treatment. When comparing current treatments for AS, stat3-p lnh showed a comparable suppression effect on osteogenesis to Janus kinase inhibitor or IL-17A blocker in AS-osteoprogenitor cells. Stat3-p lnh suppressed differentiation and mineralization of AS-osteoprogenitor cells and entheseal cells toward osteoblasts. Micro-CT analysis of hind paws revealed less new bone formation in stat3-p lnh-treated mice than vehicle-treated mice (P = 0 .00 5) . Hind paw and spinal new bone formation were similar between stat3-p lnh- and anti-IL-17A-treated SKG mice (P = 0 .874 and P = 0 .117, respectively). Conclusion. Stat-3p inhibition is a promising treatment for both inflammation and new bone formation in AS.

Automated summary

The study demonstrates that stat3-p lnh effectively suppresses chronic inflammation and bone formation in AS. Results show significant reductions in arthritis, enthesitis, spondylitis, and ileitis in the mouse model treated with stat3-p lnh. In vitro experiments also indicate decreased frequencies of inflammatory cytokine-producing cells after stat3-p lnh treatment.