HMGB1 levels were increased in the serum, synovium, and synovia. HMGB1 levels in serum of RA patients were higher than that of OA patients and correlated with disease activity scores. HMGB1 promoted osteoclast and proinflammatory factor production and accelerated the activity of metalloproteinases and plasminogen activators. HMGB1 synergized with CXCL12 in active RA patients contributing to the influx of pro-inflammatory cells. In the model of CIA, HMGB1 was also involved in neurogenic inflammation. Here, HMGB1 is linked to rheumatoid arthritis.