Immune modulation by chondroitin sulfate and its degraded disaccharide product in the development of an experimental model of multiple sclerosis
Introduction
Multiple sclerosis (MS) is viewed as an autoimmune disease, however, neither the etiology nor the mechanism of disease is fully understood, and current treatments have only modest effect. The conceptual understanding of MS rests on the animal model of experimental autoimmune encephalomyelitis (EAE). It is widely believed that MS is an inflammatory attack on myelin and neurons orchestrated by myelin specific T cells (Holmoy, 2007).
Chondroitin sulfate (CS) is a major component of the extracellular matrix of many connective tissues, including cartilage, bone, skin, ligaments and tendons. It is a sulfated glycosaminoglycan (GAG) composed of a long unbranched polysaccharide chain with a repeating disaccharide structure of N-acetylgalactosamine and glucuronic acid. CS is an ingredient found commonly in dietary supplements used as complementary and alternative medicine (CAM) to treat osteoarthritis (OA). Researchers conducted a 4-year study known as the Glucosamine/chondroitin Arthritis Intervention Trial at 16 sites across the United States and found that the popular dietary supplement combination of glucosamine plus chondroitin sulfate did not provide significant relief from osteoarthritis pain among all participants. However, a smaller subgroup of study participants with moderate-to-severe pain showed significant relief with the combined supplements (Clegg et al., 2006). A recent report also demonstrates that CS has a slight to moderate efficacy in the symptomatic treatment of OA, with an excellent safety profile (Monfort et al., 2008a). The benefit of chondroitin sulfate in patients with OA is likely the result of a number of effects including its anti-inflammatory activity (Monfort et al., 2008b). Such findings suggest that CS may play an important role as a CAM that could potentially benefit patients suffering from other autoimmune diseases such as MS.
Chondroitin sulfate proteoglycan (CSPG), a matrix protein that occurs naturally in the CNS, is considered to be a major inhibitor of axonal regeneration and is known to participate in activation of the inflammatory response. The disaccharide degradation of CSPG by a specific enzyme, chondroitinase ABC, promotes repair (Rolls et al., 2004). Thus it has been postulated that a disaccharidic degradation product of chondroitin sulfate proteoglycan (CSPG-DS), participates in the modulation of the inflammatory responses and can, therefore, promote recovery in immune-induced neuropathologies of the CNS, such as experimental autoimmune uveitis (EAU) and EAE (Rolls et al., 2006). In these disease models, the dramatic increase in T cells infiltrating the CNS is far in excess of the numbers needed for regular maintenance. It has been reported that CSPG-DS markedly alleviated the clinical symptoms of EAE and protected against the neuronal loss in EAU (Rolls et al., 2006).
Although the functions of chondroitin sulfate in OA have been extensively studies (Uebelhart, 2008, Uebelhart et al., 2006, Vangsness et al., 2009, Volpi, 2004), the role of chondroitin sulfate in EAE is still unknown. Studies on the immune modulation by chondroitin sulfate and its degraded disaccharide in EAE will provide a novel effective therapeutic target for multiple sclerosis in the patients and have great implications in the elucidation of mechanisms underlying multiple sclerosis. In the current study, we provide evidence for the first time that CS-A, which is naturally present in the central nervous system, may play a role in enhancing the clinical symptoms of EAE, whereas its degraded product, CSPG-DS, inhibits EAE development. Thus, CSPG-DS may constitute a novel drug candidate for suppressing inflammation and clinical disease in MS patients.
Section snippets
Mice
C57BL/6 mice were obtained from the National Institutes of Health (Frederick, MD). Female mice, 8–10 weeks of age, were used throughout these studies. Animals were housed in specific pathogen-free conditions, and all experiments were approved by Institutional Animal Care and Use Committee.
EAE induction
Myelin oligodendrocyte glycoprotein MOG35–55 peptide (MEVGWYRSPFSRVVHLYRNGK) was diluted in PBS to a final concentration of 3 mg/ml. Equal volumes of MOG/PBS were mixed with complete Freund's adjuvant (CFA,
Modulation of EAE development by CS-A and CSPG-DS
Chondroitin sulfate is a GAG that is widely present in animal tissues, including the CNS and when externally administered has been shown to have anti-inflammatory and chondroprotective properties (Akiyama et al., 2004). We were interested in delineating the role of chondroitin sulfate A and its degraded disaccharide product on the lymphocytic infiltration in the CNS and development of experimental autoimmune encephalomyelitis in mice. Mice received subcutaneous injection of myelin
Discussion
Chondroitin sulfate (CS) is a sulfated GAG composed of a chain of alternating sugars (N-acetylgalactosamine and glucuronic acid). It is usually found attached to proteins as part of a proteoglycan. CS is an important structural component of cartilage and provides much of its resistance to compression (Baeurlea et al., 2009). Along with glucosamine, chondroitin sulfate is a widely used dietary supplement for treatment of OA. The use of CS is somewhat controversial and recent research has
Acknowledgements
This work was supported by NIH grants R01ES09098, R01DA016545 and P01AT003961 (P. Nagarkatti); NIH grants R01AI053703, R01AI058300, and R01HL058641 (M. Nagarkatti).
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