Chondroitin sulfate

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Chemical structure of one unit in a chondroitin sulfate chain. Chondroitin-4-sulfate: R1 = H; R2 = SO3H; R3 = H. Chondroitin-6-sulfate: R1 = SO3H; R2, R3 = H.

Chondroitin sulfate is a sulfated glycosaminoglycan (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. A chondroitin chain can have over 100 individual sugars, each of which can be sulfated in variable positions and quantities. Chondroitin sulfate is an important structural component of cartilage and provides much of its resistance to compression.[1] Along with glucosamine, chondroitin sulfate has become a widely used dietary supplement for treatment of osteoarthritis.

Terminology[edit]

Chondroitin sulfate was originally isolated well before the structure was characterised, leading to changes in terminology with time.[2] Early researchers identified different fractions of the substance with letters.

Letter identification Site of sulfation Systematic name
Chondroitin sulfate A carbon 4 of the N-acetylgalactosamine (GalNAc) sugar chondroitin-4-sulfate
Chondroitin sulfate C carbon 6 of the GalNAc sugar chondroitin-6-sulfate
Chondroitin sulfate D carbon 2 of the glucuronic acid and 6 of the GalNAc sugar chondroitin-2,6-sulfate
Chondroitin sulfate E carbons 4 and 6 of the GalNAc sugar chondroitin-4,6-sulfate

"Chondroitin sulfate B" is an old name for dermatan sulfate, and it is no longer classified as a form of chondroitin sulfate.[3]

Chondroitin, without the "sulfate", has been used to describe a fraction with little or no sulfation.[4] However, this distinction is not used by all.

Although the name "chondroitin sulfate" suggests a salt with a sulfate counter-anion, this is not the case, as sulfate is covalently bonded to the sugar. Rather, since the molecule has multiple negative charges at physiological pH, a cation is present in salts of chondroitin sulfate. Commercial preparations of chondroitin sulfate typically are the sodium salt. Barnhill et al. have suggested that all such preparations of chondroitin sulfate be referred to as "sodium chondroitin" regardless of their sulfation status.[5]

Structure[edit]

Chondroitin sulfate chains are unbranched polysaccharides of variable length containing two alternating monosaccharides: D-glucuronic acid (GlcA) and N-acetyl-D-galactosamine (GalNAc). Some GlcA residues are epimerized into L-iduronic acid (IdoA); the resulting disaccharide is then referred to as dermatan sulfate.

Protein attachment[edit]

Chondroitin sulfate chains are linked to hydroxyl groups on serine residues of certain proteins. Exactly how proteins are selected for attachment of glycosaminoglycans is not understood. Glycosylated serines are often followed by a glycine and have neighboring acidic residues, but this motif does not always predict glycosylation.

Attachment of the GAG chain begins with four monosaccharides in a fixed pattern: Xyl - Gal - Gal - GlcA. Each sugar is attached by a specific enzyme, allowing for multiple levels of control over GAG synthesis. Xylose begins to be attached to proteins in the endoplasmic reticulum, while the rest of the sugars are attached in the Golgi apparatus.[6]

Sulfation[edit]

Each monosaccharide may be left unsulfated, sulfated once, or sulfated twice. In the most common scenario, the hydroxyls of the 4 and 6 positions of the N-acetyl-galactosamine are sulfated, with some chains having the 2 position of glucuronic acid. Sulfation is mediated by specific sulfotransferases. Sulfation in these different positions confers specific biological activities to chondroitin GAG chains.

Function[edit]

Chondroitin's functions depend largely on the properties of the overall proteoglycan of which it is a part. These functions can be broadly divided into structural and regulatory roles. However, this division is not absolute, and some proteoglycans have both structural and regulatory roles (see versican).

Structural[edit]

Chondroitin sulfate is a major component of extracellular matrix, and is important in maintaining the structural integrity of the tissue. This function is typical of the large aggregating proteoglycans: aggrecan, versican, brevican, and neurocan, collectively termed the lecticans.

As part of aggrecan, chondroitin sulfate is a major component of cartilage. The tightly packed and highly charged sulfate groups of chondroitin sulfate generate electrostatic repulsion that provides much of the resistance of cartilage to compression. Loss of chondroitin sulfate from the cartilage is a major cause of osteoarthritis.

Regulatory[edit]

Chondroitin sulfate readily interacts with proteins in the extracellular matrix due to its negative charges. These interactions are important for regulating a diverse array of cellular activities. The lecticans are a major part of the brain extracellular matrix, where the chondroitin sugar chains function to stabilize normal brain synapses as part of perineuronal nets. The levels of chondroitin sulfate proteoglycans are vastly increased after injury to the central nervous system where they act to prevent regeneration of damaged nerve endings. Although these functions are not as well characterized as those of heparan sulfate, new roles continue to be discovered for the chondroitin sulfate proteoglycans.

In cortical development, chondroitin sulfate is expressed by the Sub Plate and acts as a stop signal for neurons migrating from the Ventricular Zone. Neurons stopping here may then be programmed for further migration to specific layers in the cortical plate.

Medical use[edit]

Chondroitin is in dietary supplements used as an alternative medicine to treat osteoarthritis and also approved and regulated as a symptomatic slow-acting drug for this disease (SYSADOA) in Europe and some other countries.[7] It is commonly sold together with glucosamine. Chondroitin and glucosamine are also used in veterinary medicine.[8]

Pharmacology[edit]

The dosage of oral chondroitin used in human clinical trials is 800–1,200 mg per day. Most chondroitin appears to be made from extracts of cartilaginous cow and pig tissues (cow trachea and pig ear and nose), but other sources such as shark, fish, and bird cartilage are also used. Since chondroitin is not a uniform substance, and is naturally present in a wide variety of forms, the precise composition of each supplement will vary.[5] In fact, although many food supplement companies produce their products in compliance with human food processing Good Manufacturing Practice (GMP), most of them do not produce their products in compliance with the GMP regulations for pharmaceuticals, resulting in products without pharmaceutical requirements.[9] Companies have attempted to produce chondroitin from other substances but have not yet had success.

Recent testing has revealed several flaws in the older testing methods. Without knowing the source of the chondroitin (e.g., shark, porcine, or bovine) and the approximate age of the animal, it is impossible to get a reliable reference standard, and, thus, results from previous testing had yielded percentages between 50 and 400%. In 2007, David Ji et al. reported in the Journal of Analytical Chemistry an extremely accurate method of quantification. The method included using an enzyme to break the chondroitin into its individual unsaturated disaccharides, and then measuring them using HPLC with an ion-pairing column and UV detection.[10]

Clinical studies have not identified any significant side effects or overdoses of chondroitin sulfate, which suggest its long-term safety.[11] The Task Force of the European League Against Rheumatism (EULAR) committee recently granted chondroitin sulfate a level of toxicity of 6 in a 0-100 scale, confirming it is one of the safest drugs for osteoarthritis.[7] Moreover, its safety is supported by an absence of drug-drug interactions (chondroitin sulfate is not metabolized by cytochrome P450),[12] and the lack of safe alternatives for patients multi-medicated for osteoarthritis and other accompanying diseases, e.g. diabetes, hypertension, hyperlipidemia, etc.

Regulation (legal)[edit]

While it is a prescription or over-the-counter drug in 22 countries, chondroitin is regulated in the U.S. as a dietary supplement[13] by the Food and Drug Administration. In Europe, chondroitin sulfate formulations are approved as drugs with evidenced efficacy and safety demonstrated by clinical trials in osteoarthritic patients.[14] Adebowale et al. reported in 2000 that of 32 chondroitin supplements they analysed, only 5 were labeled correctly, and more than half contained less than 40% of the labeled amount.[15] With the introduction of GMP regulations for dietary supplements in 2008, chondroitin sulfate preparations are subject in the US to mandatory labeling standards as well as testing requirements for identity, purity, strength, and composition.[citation needed] United States Pharmacopoeia (USP) testing standards for the identification and quantification of chondroitin are well-established.[citation needed]

Bioavailability and pharmacokinetics[edit]

Pharmacokinetic studies performed on humans and experimental animals after oral administration of chondroitin sulfate revealed that it can be absorbed orally. Chondroitin sulfate shows first-order kinetics up to single doses of 3,000 mg.[16][17][18][19] Multiple doses of 800 mg in patients with osteoarthritis do not alter the kinetics of chondroitin sulfate. The bioavailability of chondroitin sulfate ranges from 15% to 24% of the orally administered dose. More particularly, on the articular tissue, Ronca et al.[20] reported that chondroitin sulfate is not rapidly absorbed in the gastro-intestinal tract and a high content of labeled chondroitin sulfate is found in the synovial fluid and cartilage.

Mechanisms of action[edit]

The effect of chondroitin sulfate in patients with osteoarthritis is likely the result of a number of reactions including its anti-inflammatory activity, the stimulation of the synthesis of proteoglycans and hyaluronic acid, and the decrease in catabolic activity of chondrocytes inhibiting the synthesis of proteolytic enzymes, nitric oxide, and other substances that contribute to damage cartilage matrix and cause death of articular chondrocytes. A recent review summarizes data from relevant reports describing the biochemical basis of the effect of chondroitin sulfate on osteoarthritis articular tissues.[21] The rationale behind the use of chondroitin sulfate is based on the belief that osteoarthritis is associated with a local deficiency or degradation of natural substances, including internal chondroitin sulfate.

Recently, new mechanisms of action have been described for chondroitin sulfate. In an in vitro study, chondroitin sulfate reduced the IL-1β-induced nuclear factor-kB (NF-κB) translocation in chondrocytes.[22] In addition, chondroitin sulfate has recently shown a positive effect on osteoarthritic structural changes occurred in the subchondral bone.[23]

A review published in the Annals of Rheumatic Diseases describes all the documented evidence regarding the mechanisms of action of chondroitin sulfate[24]

Clinical trials for osteoarthritis[edit]

Many randomized controlled trials have been conducted with mixed results. These trials have been summarized:

  • Reichenbach et al.[25] used explicit methods to conduct and report[26] a systematic review of 20 trials and concluded "large-scale, methodologically sound trials indicate that the symptomatic benefit of chondroitin is minimal or nonexistent. Use of chondroitin in routine clinical practice should therefore be discouraged."
  • Bruyere et al.[27] without using explicit methodology for reviewing trials concluded "there is compelling evidence that glucosamine sulfate and chondroitin sulfate may interfere with progression of OA."

The major trial included in the two reviews above was the GAIT study.[28] GAIT was funded by National Institutes of Health to test the effects of chondroitin and glucosamine on osteoarthritis of the knee. This multicenter, placebo-controlled, double-blind, six-month-long trial found that glucosamine plus chondroitin had no statistically significant effect on symptoms of osteoarthritis in the overall group of osteoarthritis patients. However, in the moderate-to-severe pain subgroup, the combination of chondroitin and glucosamine was found to be subjectively more effective (in 25% of the patients) in treating pain than celecoxib or chondroitin and glucosamine taken individually. Due to small sample sizes in the sub-group (roughly 250 people), the researchers concluded that this needs further validation. The study also found chondroitin sulfate to have no significant effect in reducing joint swelling, effusion, or both. These results indicate that glucosamine and chondroitin do not effectively relieve osteoarthiritic pain in the overall group of osteoarthritis patients, though it may be an effective treatment for those suffering from moderate-to-severe pain.[1] In a follow-up study, 572 patients from the GAIT trial continued the supplementation for 2 years. After 2 years of supplementation with glucosamine and chondroitin sulfate, alone or in combination, there was no benefit in slowing the loss of cartilage, in terms of joint space width, when compared to a placebo.[29] Further, in another 2-year follow-up study, there was no significant pain reduction or improved function when compared to a placebo.[30] Some of the researcher's ties to Pfizer (which makes celecoxib), have brought into question the validity of the study. [2]

Clinical practice guidelines based on trials prior to publication of the negative review by Reichenbach[25] and the negative GAIT trial[28] recommended the use of chondroitin. The OARSI (OsteoArthritis Research Society International) recommended chondroitin sulfate as the second-most-effective treatment for moderate cases of osteoarthritis (although the guidelines were published in 2008, the developers closed their search date in January 2006 – prior to the GAIT trial).[31] Likewise, the European League Against Rheumatism (EULAR) supported the usefulness of chondroitin sulfate in the management of knee osteoarthritis and grants the highest level of evidence, 1A, and strength of the recommendation, A, to this product.[32]

Contamination in heparin[edit]

On Wednesday, March 19, 2008 the U.S. Food and Drug Administration (FDA) identified "oversulfated chondroitin sulfate" as a contaminant in heparin originating from China.[33]

In this regard, "it is very important to remark on the relevant chemical differences between the chondroitin sulfate formulation approved in Europe as a drug and considered the reference product, and the "oversulfated chondroitin sulfate" identified as a contaminant in heparin originating from China."

The "oversulfated chondroitin sulfate" is not a product extracted from biological sources; it is synthesized through a sulfation reaction from the biological molecule. This is a semi-synthesis process that uses naturally derived chondroitin sulfate as a reagent in combination with various potentially dangerous chemicals, though their significance in the toxicity of "oversulfated chondroitin sulfate" is not known.

The resulting product contains 3 or 4 sulfate groups per disaccharide, and, therefore, its structure differs considerably from the original one (see #Sulfation section above). Furthermore, analysis of the contaminant unexpectedly revealed an unusual type of sulfation not found in any natural sources of chondroitin sulfate. In addition, a tetrasulfated disaccharide repeat unit has not been isolated to date from animal tissues[34]

Thus, chondroitin sulfate is merely the substrate of the reaction: The final, oversulfated molecule constitutes a new entity, whose pharmacological and clinical properties are most likely very different from the biological molecule, as it is demonstrated in a recent article published in New England Journal of Medicine. In this study,[35] Sasisekharan and colleagues showed that the oversulfated chondroitin sulfate (OSCS) found in contaminated lots of unfractionated heparin, as well as a synthetically generated OSCS reference standard, directly activated the kinin–kallikrein pathway in human plasma, which can lead to the generation of bradykinin, a potent vasoactive mediator. In addition, OSCS induced generation of C3a and C5a, potent anaphylatoxins derived from complement proteins. Chondroitin sulfate A was also tested and it showed no induction of amidollytic activity. Screening of plasma samples from various species indicated that swine and humans are sensitive to the effects of OSCS in a similar manner. OSCS-containing heparin and synthetically derived OSCS-induced hypotension associated with kallikrein activation when administered by intravenous infusion in swine. In contrast, none of the three pigs treated with chondroitin sulfate A showed any significant changes in blood pressure or heart rate.

See also[edit]

References[edit]

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  34. ^ Guerrini, M.; Beccati, D.; Shriver, Z.; Naggi, A.; Viswanathan, K.; Bisio, A.; Capila, I.; Lansing, C.; Guglieri, S.; Fraser, B.; Al-Hakim, A.; Gunay, N. S.; Zhang, Z.; Robinson, L.; Buhse, L.; Nasr, M.; Woodcock, J.; Langer, R.; Venkataraman, G.; Linhardt, R. J.; Casu, B.; Torri, G.; Sasisekharan, R. (Jun 2008). "Oversulfated chondroitin sulfate is a contaminant in heparin associated with adverse clinical events". Nature Biotechnology 26 (6): 669–675. doi:10.1038/nbt1407. ISSN 1087-0156. PMC 3491566. PMID 18437154.  edit
  35. ^ Kishimoto, K.; Viswanathan, K.; Ganguly, T.; Elankumaran, S.; Smith, S.; Pelzer, K.; Lansing, C.; Sriranganathan, N.; Zhao, G.; Galcheva-Gargova, Z.; Al-Hakim, A.; Bailey, G. S.; Fraser, B.; Roy, S.; Rogers-Cotrone, T.; Buhse, L.; Whary, M.; Fox, J.; Nasr, M.; Dal Pan, G. J.; Shriver, Z.; Langer, R. S.; Venkataraman, G.; Austen, K. F.; Woodcock, J.; Sasisekharan, R. (Jun 2008). "Contaminated heparin associated with adverse clinical events and activation of the contact system". The New England Journal of Medicine 358 (23): 2457–2467. doi:10.1056/NEJMoa0803200. ISSN 0028-4793. PMC 3778681. PMID 18434646.  edit

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