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.

Evidence of Disruption in Neural Regeneration in Dry Eye Secondary to Rheumatoid Arthritis

“…Noteworthily, according to the altered glycan theory of autoimmunity, every single autoimmune disease has its own glycan profile [46]. Accordingly, the role of proteoglycans in the pathogenesis of RA and resulting proteoglycan-modulating therapies have been the foci of recent research [47]. Furthermore, it is important to note that degradation of proteoglycans biomechanically resembles static compression [48], and this could have molecular implications for indentation and mechanotransduction of piezoelectric channels in the cell membrane.…”

Proprotein Convertase Subtilisin/Kexin 6 in Cardiovascular Biology and Disease

“…Analysis of Pcsk6 KO mice substantiates a role of PCSK6 in aggrecan degradation and osteoarthritis [ 77 ]. Aggrecan is a proteoglycan with abundant chondroitin and keratan sulfate chains [ 78 , 79 ]. It aggregates on hyaluronan filaments in the extracellular matrix of articular cartilage, protecting the joint from the impact of compressive forces [ 78 , 79 ].…”

“…Aggrecan is a proteoglycan with abundant chondroitin and keratan sulfate chains [ 78 , 79 ]. It aggregates on hyaluronan filaments in the extracellular matrix of articular cartilage, protecting the joint from the impact of compressive forces [ 78 , 79 ]. Increased aggrecan degradation is a key factor in the pathogenesis of osteoarthritis [ 80 ].…”

Significance of Type II Collagen Posttranslational Modifications: From Autoantigenesis to Improved Diagnosis and Treatment of Rheumatoid Arthritis

“…Some of them are ubiquitously expressed—glucose-6-phosphate isomerase (G6PI) [ 17 ], heterogeneous nuclear ribonucleoprotein-A2 (RA33) [ 18 , 19 ], immunoglobulin binding protein (BiP) [ 20 ], and citrullinated proteins (fibrinogen, filaggrin, vimentin, α-enolase, tenascin-C, histones, etc.) [ 21 , 22 , 23 ]—while others are joint-specific—COL2 [ 24 , 25 , 26 ], aggrecan [ 27 , 28 ], human cartilage glycoprotein 39 [ 29 ], and cartilage oligomeric matrix protein (COMP) [ 30 ]. Considering the heterogeneous nature of RA, it is possible that different antigens cause and perpetuate the disease in patients from different subgroups.…”