Emerging proteoglycans and proteoglycan-targeted therapies in rheumatoid arthritis

Rheumatoid arthritis (RA) is a common autoimmune disease that causes inflammation of the joints and damage to the cartilage and bone. The pathogenesis of RA is characterized in many patients by the presence of antibodies against citrullinated proteins. Proteoglycans are key structural elements of extracellular matrix in the joint articular cartilage and synovium and are secreted as lubricants in the synovial fluid. Alterations of proteoglycans contribute to RA pathogenesis. Proteoglycans such as aggrecan can be citrullinated and become potential targets of the rheumatoid autoimmune response. Proteoglycans are also upregulated in RA joints and/or undergo alterations of their regulatory functions over cytokines and chemokines, which promotes inflammation and bone damage. Recent studies have aimed to not only clarify these mechanisms but also develop novel proteoglycan-modulating therapeutics. These include agents altering the function and signaling of proteoglycans as well as tolerizing agents targeting citrullinated aggrecan. This mini-review summarizes the most recent findings regarding the dysregulation of proteoglycans that contributes to RA pathogenesis and the potential for proteoglycan-modulating agents to improve upon current RA therapy.