Immunomodulatory and Anti-inflammatory Effects of Chondroitin Sulphate

Chondroitin sulphate (CS) is the main disaccharide unit found naturally in glycosaminoglycan (GAG) formed by the 1–3 linkage of D-glucuronic acid to N-acetylgalactosamine.¹ It exists in the extracellular matrix surrounding the chondrocytes, skin, blood vessels, ligaments and tendons and is an important component of proteoglycans.^2,3 These proteoglycans exhibit viscoelastic and hydration properties and thereby contribute to the proper functioning and protection of articular cartilage. ^4,5 For decades, CS, as a symptomatic slow-acting drug for osteoarthritis (SYSADOA), has been used in osteoarthritis (OA) therapy based on the rationale that CS decreases with ageing in patients with OA. However, recent studies show that CS reduces inflammatory signs while delaying the progression of cartilage destruction in OA patients.^6–10 Therefore, CS appears to actively affect clinical outcomes in OA. As the antiinflammatory effects of CS are studied and its mechanisms of action are elucidated, CS may reveal its potential to treat other common inflammatory diseases.

Pro-inflammatory Mediators, Articulate Surfaces and Chondroitin Sulphate
Although the exact mechanism of action of CS has yet to be fully elucidated, it has been shown that CS exerts a benefical effect on the chondrocytes, synovial membrane and subchondral bone of a joint. These components are all affected in OA (see Figure 1). Repeated trauma to an articulation results in the release of proinflammatory mediators into the extracellular matrix. These mediators include cytokines such as interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α) (see Figure 2). The pro inflammatory mediators play a pivotal role in the development of OA. In chondrocytes, IL-1β binds to cell surface receptors and activates various signalling pathways, including the extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen activated protein kinase (p38MAPK) pathways, which activate downstream inflammatory pathways within the cell. One key consequence is the activation and nuclear translocation of the transcription factor nuclear factor-κB (NF-κB). By binding to consensus sequences of pro-inflammatory genes, this transcription factor initiates and maintains the inflammatory reaction (see Figure 2).^11–13 An in vitro study14 found that CS inhibited phosphorylation and activation of both ERK1/2 and p38MAPK while reducing the nuclear translocation of NF-κB, supporting an anti-inflammatory effect of CS within chondrocytes. ¹⁴

In OA, the synovial tissue of an affected articulation exhibits the presence of activated fibroblast-like synoviocytes (FLS), macrophages, mast and T cells and other inflammatory markers. FLS release numerous pro inflammatory cytokines, including IL-1β, IL-6, IL-8 and the receptor activator of NF-κB ligand (RANKL).¹⁵ NF-κB activation is thought to play a key role in the development of synovitis as it alters the phenotype of synoviocytes into aggressive tumour-like FLS with the ability to secrete additional cytokines.^16–18 Patients with knee OA were shown to respond favourably to CS, with a reduction in the symptoms of synovitis after 24 weeks of treatment (p=0.01). ⁶ Possibly, CS reduces the synovitis in a similar manner to its effect on chondrocytes, where CS inhibits ERK1/2 and p38MAPK and NF-κB signalling, diminishing the inflammatory reaction.

Subchondral bone is thought to be affected in OA as a result of abnormal osteoblast metabolism. ¹⁹ A recent study demonstrated that in human subchrondral bone osteoblasts, CS upregulates osteoprotegerin (OPG) expression while decreasing RANKL expression, thereby increasing the ratio of OPG/RANKL.²⁰ This indicates that CS will impede the increase in osteoclasts and therefore reduce bone resorption. This effect of CS on subchondral bone may again be related to the inhibition of the activation of the ERK1/2 pathway known to precipitate RANKL production.²¹

Since chondrocytes, the synovial membrane and the subchondral bone are all affected in OA, it may be relevant to use a treatment that has an effect on all three components. Having demonstrated positive immunomodulatory effects in each part of the joint, CS appears to be a logical approach in this disease.