Emerging proteoglycans and proteoglycan-targeted therapies in rheumatoid arthritis

Abstract

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.

Keywords: aggrecan; citrullination; proteoglycans; rheumatoid arthritis; syndecan.

Figure 1.

Proteoglycans contribute to adaptive and innate immune responses in RA. Proteoglycans are prevalent in normal articular cartilage where they interact with collagen fibers and hyaluronan creating a negatively charged aggregate that is highly hydrophilic and important for the biomechanical properties of the joint (left). In RA, aggrecan is degraded, proinflammatory cytokines bind proteoglycans and cause the trafficking of immune cells to the joint, and citrullinated aggrecan (citrullination shown in orange) is presented by antigen-presenting cells and activates T cells (right). (Created with Biorender.com). RA, rheumatoid arthritis; ECM, extracellular matrix; SF, synovial fibroblasts.

Figure 2.

Structure of proteoglycans implicated in RA and their subcellular location. The legend is located in the upper left-hand box. Upregulated in RA (green), downregulated (red), unknown, or no change (yellow). PGs differ by type and number of glycosaminoglycan chains. Aggrecan and versican are usually found bound to a hyaluronan backbone. SLRPs share a similar structure with 2-7 keratan sulfate chains. Membrane-bound PGs can be shed and consequently also found in the ECM. (Created with Biorender.com). ECM, extracellular matrix; PG, proteoglycan; RA, rheumatoid arthritis; SLRP, small leucine-rich proteoglycan; GPI, glycophosphatidylinositol.

Figure 3.

Current therapeutic approaches to modulate PG activity. (Created with Biorender.com). PG, proteoglycan. GAG, glycosaminoglycan; PTPRS, protein tyrosine phosphatase receptor type S; cit-Agg, citrullinated aggrcan; IL1R1, interleukin-1 receptor type 1.