Pain in rheumatoid arthritis: Emerging role of high mobility group box 1 protein-HMGB1

Rheumatoid arthritis (RA) is a chronic inflammatory disease where pain, driven by both inflammatory and non-inflammatory processes, is a major concern for patients. This pain can persist even after joint inflammation subsides. High mobility group box-1 (HMGB1) is a non-histone-DNA binding protein located in the nucleus that plays a key role in processes such as DNA transcription, recombination, and replication. HMGB1 can be released into the extracellular space through both passive and active mechanisms. Extracellular HMGB1 contributes to synovial inflammation, bone degradation, and the production of cytokines in RA by binding to toll-like receptors (TLRs) and receptors for advanced glycation end products (RAGE). It also forms complexes with molecules like lipopolysaccharide (LPS) and IL-1β, amplifying inflammatory responses. Due to its central role in these processes, HMGB1 is considered a promising therapeutic target in RA. It also acts as a nociceptive molecule in mediating pain in diseases such as diabetes and bone cancer. In this review, we explore how HMGB1 contributes to chronic pain in RA, supported by both in vitro and in vivo models. We begin by providing an overview of the mechanisms of pain in RA, the structure of HMGB1, its release mechanisms, and the therapeutic potential of targeting HMGB1 in RA. Following this, we highlight its role in peripheral and central pain sensitization through direct activation of the TLR4/MAPK/NF-κB pathway, as well as indirectly through downstream mediators, underscoring its potential as a target for managing RA pain.