Chondroitin Sulfate as Anti-Inflammatory

Osteoarthritis.

Osteoarthritis is characterized by focal areas of loss of articular cartilage, with varying degrees of osteophyte formation, subchondral bone change, and synovitis1. 

The pathophysiology of osteoarthrosis remains controversial. It has been proposed that continuous use of the joint implies multiple microtraumas to the articular cartilage and formation of fibronectin and extracellular matrix fragments (EMFs).

   

Summary

Osteoarthritis is primarily characterized by areas of destruction of articular cartilage and by synovitis. Articular damage and synovitis are secondary to a local increase of pro-inflammatory cytokines (interleukin-1b and tumor necrosis factor-a), enzymes with proteolytic activity (matrix.

metalloproteinases), and enzymes with pro-inflammatory activity (cyclooxygenase-2 and nitric oxide synthase-2). Enhanced expression of these proteins in chondrocytes and in synovial membrane appears associated to the activation and nuclear translocation of nuclear factorkB ( NF-kB). 

Chondroitin sulfate (CS) prevents joint space narrowing and reduces joint swelling and effusion. To produce these effects, CS elicits an anti-inflammatory effect at the chondral and synovial levels. 

Chondroitin sulfate (CS) and its disaccharides reduce NF-kB nuclear translocation, probably by diminishing extracellular signal regulated kinase1/2, p38mitogen-activated protein kinase, and c-Jun N-terminal kinase activation. 

This review discusses the evidence supporting that CS pleiotropic effects in synoviocytes and chondrocytes are primarily due to a common mechanism, e.g., the inhibition of NF-kB nuclear translocationª 2008 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Fibronectin fragments (FN-f) contribute to cartilage destruction 2 by binding to a5b1 integrin receptor of the chondrocyte with the subsequent activation of protein kinase C (PKC), proline-rich tyrosine kinase-2, extracellular signal regulated kinase1/2 (ERK1/2), p38mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK), that trigger the nuclear translocation of activated protein-1 (AP-1) and nuclear factor-kB (NF-kB), and enhanced expression of matrix metalloproteinases (MMPs), MMP-3 and MMP-133.

Synovitis is reflected by several of the signs and symptoms of osteoarthritis, such as swelling and effusion, pain, redness, and stiffness7. In patients with osteoarthritis, changes in pain are closely associated with the changes in synovitis but not to cartilage loss9.

Chondroitin sulfate (CS) in osteoarthritis, clinical evidence.

On the one hand, the decrease in pain and swelling may be explained by an anti-inflammatory effect of Chondroitin sulfate, probably through diverse mechanisms such as diminishing the expression of phospholipase A2 (PLA2) 17, of cyclooxygenase-2 (COX-2), and the concentrations of prostaglandin E2 (PGE2) 18,19. In joints, CS reduces the concentrations of pro-inflammatory cytokines, such as TNF-a20 and IL-1b21, and joint and systemic concentrations of NO 19,22 and of reactive oxygen species (ROS) 20.

the fact that in chondrocytes, CS diminishes IL-1b-mediated increase in MMP-218, MMP-318, MMP-918,19,21, MMP-1318,19, and MMP-1418. It has been documented that hyaluronan and mixtures of low concentrations of CS and glucosamine are able to prevent the release of MMP-3 and MMP-13 triggered by FN-f23,24. In subchondral bone, CS increases osteoprotegerin (OPG) and reduces the expression of receptor activator of NF-kB ligand (RANKL), effects that may result in the reduction of the resorptive activity in subchondral bone25.

Effect of Chondroitin Sulfate on articular cartilage, mechanism of action.

The presence of synovitis at early stages of osteoarthritis is associated with a more destructive and rapid progression of the disease7. Independently of the sequence of events in the apparition of osteoarthritis, e.g., cartilage damage or synovitis at the origin of osteoarthritis, cartilage damage and synovitis are present in a great proportion of patients, both contribute to the signs.

Randomized clinical trials have shown that CS reduces pain and improves joint function11e13, reduces joint swelling and effusion14, and prevents joint space narrowing of the knee11,13 and fingers15,16 more effectively than placebo. According to these effects, CS has been classified as a symptomatic slow-acting drug in osteoarthritis (SYSADOA) and a structure/disease modifying anti-osteoarthritis drug (S/DMOAD) 11,15.

The presence of synovitis at early stages of osteoarthritis is associated with a more destructive and rapid progression of the disease7. There is evidence that a subset of patients with osteoarthritic joint disease present synovitis and synovial hyperplasia without cartilage damage and EMFs, suggesting that in some patients, synovitis is a very early or the initial event in the development of osteoarthritis10. Independently of the sequence of events in the apparition of osteoarthritis, e.g., cartilage damage or synovitis at the origin of osteoarthritis, cartilage damage and synovitis are present in a great proportion of patients, both contribute to the signs and symptoms of osteoarthritis and both should be the target of therapy.

On the other hand, EMFs, IL-1b, and TNF-a released into the synovial fluid will activate macrophages, mastocytes, and synoviocytes in the synovial membrane originating the synovitis. Activation of synovial cells will result in a further release of IL-1b, TNF-a and MMPs that will contribute to the destruction of the cartilage matrix1,4 e6 (Fig. 2).

There is clinical evidence showing that osteoarthritis and synovitis are associated.

ª 2008 Osteoarthritis Research Society International. Synovitis is reflected by several of the signs and symptoms of osteoarthritis, such as swelling and effusion, pain, redness, and stiffness7. In patients with osteoarthritis, changes in pain are closely associated with the changes in synovitis but not to cartilage loss9.

In chondrocytes, increased expression of MMPs is accompanied by an enhanced synthesis of pro-inflammatory cytokines, essentially interleukin-1b (IL-1b) and tumor necrosis factor-a (TNF-a), which will sustain the activation of chondrocytes and moreover, will further promote the formation of MMPs, aggrecanase, reactive oxygen intermediates, nitric oxide, and lipid-derivative inflammatory mediators such as leukotrienes and prostaglandins; these substances will enhance the catabolic activity of the chondrocytes and cause the destruction of the cartilage matrix.

Keywords: Chondroitin sulfate, Disaccharides, Osteoarthritis, Inflammation, NF-kB, Signal transduction.


Via:Arthritis.org