Chondroitin sulfate possesses novel mechanisms of action
Structure of chondroitin sulfate influences its absorption, according to a number of studies.
In healthy cartilage, a superb equilibrium exists between the functions of the chondrocyte and elements of the matrix. In the presence of an aggression, this equilibrium is destabilized, and the de novo synthesis of the matrix is reduced and degradation is increased. The net result is necrosis or apoptosis of the cartilage cells.
Chondroitin sulfate reduces inflammatory signs and symptoms and delays the progression of cartilage destruction in patients with osteoarthritis.1-5 According to animal and in vitro studies, this response results from the combination of numerous effects (Table).
Chondroitin sulfate increases the synthesis of cartilage matrix components such as hyaluronic acid and proteoglycans6-11 and reduces the degradation of cartilage matrix components, specifically collagen II, glycosaminoglycans (GAG) and proteoglycans (PG),7,12-14 and reduces necrosis and apoptosis of chondrocytes.15,16
On the other hand, chondroitin sulfate reduces the activity of collagenase, N-acetylglucosaminidase, aggrecanase 1 and 2, matrix metalloproteinase (MMP) 3, MMP-9, MMP-13, MMP-14, cathepsin B and elastase.17-22 Chondroitin sulfate elicits an anti-inflammatory effect probably through diverse mechanisms such as decreasing nuclear factor B (NF-B) nuclear translocation, diminishing the expression of cyclo-oxygenase-2 (COX-2) and phospholipase A2, and reducing the concentrations of tumor necrosis factor- (TNF-), interleukin-1 (IL-1), prostaglandin E2 (PGE2), nitric oxide and reactive oxygen species (ROS).8,9,16,19,20,23-25
The structure and properties of polysaccharides strongly influence their absorption and bioavailability if taken orally.
Proof of action
A recent study analyzed the histology of left ankle joints in rats fed dietary bars containing placebo, chondroitin sulfate or a combination of chondroitin sulfate and glucosamine sulfate.19 The rats also received saline or an injection of Freund’s complete adjuvant.
Source: du Souich P
In absence of chondroitin sulfate or the combination of chondroitin sulfate and glucosamine, the injection of Freund’s adjuvant produced a clear deterioration of the cartilage, e.g. cartilage thickness decreased. In rats fed chondroitin sulfate or the combination of chondroitin sulfate and glucosamine sulfate, the structures of the cartilage resembled those of healthy animals. In addition, the decrease in thickness was less pronounced in rats fed chondroitin sulfate and absent in rats receiving the chondroitin sulfate/glucosamine combination. This study clearly proves that chondroitin sulfate and glucosamine protect the cartilage.
Another study examined the effect of glucosamine and chondroitin sulfate concentrations on inducible nitric oxide synthase (iNOS), COX-2 messenger RNAs (mRNA), and PGE2.25 IL-1 increased iNOS and COX-2 mRNAs and PGE2 concentrations, an effect that was almost completely abrogated by both chondroitin sulfate and glucosamine. These results provide an explanation for some of the drugs’ anti-inflammatory properties.
Another study documented the effect of glucose, glucuronic acid, N-acetylglucosamine, N-acetylgalactosamine, N-acetylmannosamine and glucosamine on levels of nitric oxide in human articular chondrocytes stimulated with IL-1.23 Researchers reported that N-acetylgalactosamine, glucosamine and N-acetylglucosamine prevented the increase in nitric oxide. Glucose, glucuronic acid and N-acetylmannosamine did not modify the production of nitric oxide. This study confirms the results of others showing that chondroitin sulfate reduces iNOS mRNA.25 It is noteworthy that chondroitin sulfate is a long chain of disaccharides of glucuronic acid and N-acetylgalactosamine with sulfates in positions 4 and 6. These studies shed light on the mechanisms underlying the anti-inflammatory and anti-apoptotic effects of chondroitin sulfate.
Chondroitin sulfate reduces the concentrations of reactive species20,24,25 and diminishes the translocation of NF-B (unpublished results). These findings could factor into the reduction of MMPs, COX-2, IL-1 and TNF-, thereby decreasing the progression of osteoarthritis. Chondroitin sulfate also elicits an effect on the nucleus by activating the formation of proteoglycans and hyaluronic acid.6-11
We still do not understand the full mechanism of action of chondroitin sulfate underlying the clinical response of osteoarthritis. One of the most intriguing phenomenon is how chondroitin sulfate can elicit an intracellular effect and whether chondroitin sulfate degradation products (shorter chains of disaccharides) contribute to this effect. One of the potential gates used by chondroitin sulfate to gain access into the cell could be the CD44 receptor, which is also responsible for proteoglycans degradation.26-29 Finally, taking into account that IL-1 and fibronectin proteolytic fragments (FN-f) elicit identical effects in the chondrocyte, e.g. activation of the Erk1/2, p38MAPK, NF-B, MMP-13, MMP-3 and aggrecanases, we may hypothesize that the mechanism of action of chondroitin sulphate could involve extracellular blockade of FN-f receptors, the receptor for advanced glycation end products RAGE, the Toll-like receptor 2 TLR2, and the 51 fibronectin receptor.30-32
- Clegg DO, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795-808.
- Michel BA, et al. Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: A randomized, controlled trial. Arthritis Rheum. 2005;52:779-786.
- Uebelhart D, et al. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo. Osteoarthritis Cartilage. 2004;12:269-276.
- Richy F, et al. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis. Arch Intern Med. 2003;163:1514-1522.
- Leeb BF, et al. A metaanalysis of chondroitin sulfate in the treatment of OA. J Rheumatol. 2000;27:205-211.
- Omata T, et al. Effects of chondroitin sulfate-C on bradykinin-induced proteoglycan depletion in rats. Arzneimittelforschung. 1999;49:577-581.
- Uebelhart D, et al. Effects of oral chondroitin sulfate on the progression of knee osteoarthritis: a pilot study. Osteoarthritis Cartilage. 1998;6 Suppl A:6-13.
- Bassleer CT, et al. Effects of chondroitin sulfate and interleukin-1 on human articular chondrocytes cultivated in clusters. Osteoarthritis Cartilage. 1998;6:196-204.
- Ronca F, et al. Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage. 1998;6 Suppl A:14-21.
- Nishikawa H, et al. Influences of sulfated glycosaminoglycans on biosynthesis of hyaluronic acid in rabbit knee synovial membrane. Arch Biochem Biophys. 1985;240:146-153.
- Nishikawa H, et al. Glycosaminoglycan polysulfate-induced stimulation of hyaluronic acid synthesis in rabbit knee synovial membrane: Involvement of binding protein and calcium ion. Arch Biochem Biophys. 1988;266:201-209 .
- Cho SY, et al. Effects of low molecular weight chondroitin sulfate on type II collagen-induced arthritis in DBA/1J mice. Biol Pharm Bull. 2004;27:47-51.
- Dechant JE, et al. Effects of glucosamine hydrochloride and chondroitin sulphate, alone and in combination, on normal and interleukin-1 conditioned equine articular cartilage explant metabolism. Equine Vet J. 2005;37:227-231.
- Bassleer C, et al. In-vitro evaluation of drugs proposed as chondroprotective agents. Int J Tissue React. 1992;14:231-241.
- Campo GM, et al. Purified human plasma glycosaminoglycans limit oxidative injury induced by iron plus ascorbate in skin fibroblast cultures. Toxicol In Vitro. 2005;19:561-572.
- Conrozier T, [Chondroitin sulfates (CS 4&6): practical applications and economic impact]. Presse Med. 1998;27:1859-1861.
- Chan PS, et al. Effect of glucosamine and chondroitin sulfate on regulation of gene expression of proteolytic enzymes and their inhibitors in interleukin-1-challenged bovine articular cartilage explants. Am J Vet Res. 2005;66:1870-1876.
- Monfort J, et al. Chondroitin sulfate and hyaluronic acid (500-730 kda) inhibit stromelysin-1 synthesis in human osteoarthritic chondrocytes. Drugs Exp Clin Res. 2005;31:71-76.
- Chou MM, et al. Effects of chondroitin and glucosamine sulfate in a dietary bar formulation on inflammation, interleukin-1, matrix metalloprotease-9, and cartilage damage in arthritis, Exp Biol Med. 2005;230:255-262.
- Orth MW, et al. Inhibition of articular cartilage degradation by glucosamine-HCI and chondroitin sulphate. Equine Vet J Suppl. 2002;34:224-229.
- Baici A, Lang A. Cathepsin B secretion by rabbit articular chondrocytes: modulation by cycloheximide and glycosaminoglycans. Cell Tissue Res. 1990;259:567-573.
- Baici A, Bradamante P. Interaction between human leukocyte elastase and chondroitin sulfate. Chem Biol Interact. 1984;51:1-11.
- Shikhman AR, et al. N-acetylglucosamine prevents IL-1-mediated activation of human chondrocytes. J Immunol. 2001;166:5155-5160.
- Campo GM, et al. Efficacy of treatment with glycosaminoglycans on experimental collagen-induced arthritis in rats. Arthritis Res Ther. 2003;5:R122-R131.
- Chan PS, et al. Glucosamine and chondroitin sulfate regulate gene expression and synthesis of nitric oxide and prostaglandin E2 in articular cartilage explants. Osteoarthritis Cartilage. 2005;13:387-394.
- Stern R. Hyaluronan catabolism: a new metabolic pathway. Eur J Cell Biol. 2004;83:317-325.
- Knudson CB, Knudson K. Hyaluronan and CD44: modulators of chondrocyte metabolism. Clin Orthop Relat Res. 2004;427:S152-162.
- Knudson W, Loeser RF. CD44 and integrin matrix receptors participate in cartilage homeostasis. Cell Mol Life Sci. 2002;59:36-44.
- Tian JY, et al. Regulation of no synthesis induced by inflammatory mediators in RAW264.7 cells: collagen prevents inhibition by osteopontin. Cytokine. 2000;12:450-457.
- Loeser RF, et al. Articular chondrocytes express the receptor for advanced glycation end products: potential role in osteoarthritis. Arthritis Rheum. 2005;52:2376-2385.
- Su S-L, et al. Expression and regulation of Toll-like receptor 2 by IL-1 and fibronectin fragments in human articular chondrocytes. Osteoarthritis Cartilage. 2005;13:879-886.
- Homandberg GA, et al. Fibronectin fragments active in chondrocytic chondrolysis can be chemically cross-linked to the alpha5 integrin receptor subunit. Osteoarthritis Cartilage. 2002;10:938-949.