glucosamine chondroitin

Chondroitin sulfate is a sulfated glycosaminoglycan (GAG) composed of a chain of alternating sugars (N-acetyl-galactosamine 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. Understanding the functions of such diversity in chondroitin sulfate and related glycosaminoglycans is a major goal of glycobiology. Chondroitin sulfate is a major structural component of cartilage and provides much of its resistance to compression. Along with glucosamine, chondroitin sulfate has become a widely used dietary supplement for treatment of osteoarthritis.

Terminology

Chondroitin sulfate was originally isolated well before the structure was characterised, leading to changes in terminology with time.^[1] Early researchers identified different fractions of the substance with letters.

• Chondroitin sulfate A refers to CS predominantly sulfated at carbon 4 of the GalNAc sugar (chondroitin-4-sulfate).
• Chondroitin sulfate B is now referred to as dermatan sulfate.
• Chondroitin sulfate C refers to CS predominantly sulfated at carbon 6 of the GalNAc sugar (chondroitin-6-sulfate).
• Chondroitin sulfate D refers to CS predominantly sulfated at carbon 2 of the GlcA and 6 of the GalNAc sugar (chondroitin-2,6-sulfate).
• Chondroitin sulfate E refers to CS predominantly sulfated at carbons 4 and 6 of the GalNAc sugar (chondroitin-4,6-sulfate).

• Chondroitin, without the "sulfate", has been used to describe a fraction with little or no sulfation.^[2] 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 attached 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.^[3]

Structure

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

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. Empirically, 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.^[4]

Sulfation

Each monosaccharide may be left unsulfated, sulfated once, or sulfated twice. Most commonly the hydroxyls of the 4 and 6 positions of the N-acetyl-galactosamine are sulfated. Sulfation is mediated by specific sulfotransferases.

Function

Chondroitin's functions largely depend 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

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

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

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. 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 the nervous system, chondroitin sulfate proteoglycans regulate the growth and development of the nervous system as well as the nervous system response to injury.

Medical use

Chondroitin is an ingredient found commonly in dietary supplements used as an alternative medicine to treat osteoarthritis. It is commonly sold together with glucosamine.

Pharmacology

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.^[3] While it is a prescription or over-the-counter drug in 22 countries, chondroitin is regulated in the U.S. as a food product by the Food and Drug Administration. As a result, there are no mandatory standards for formulation, and no guarantee that the product is correctly labelled. 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.^[5] However, United States Pharmacopoeia (USP) testing standards now exist for the identification and quantification of chondroitin.

Clinical studies have not identified any significant side effects or overdoses of chondroitin sulfate.

Clinical trials

Due to the popularity of the glucosamine-chondroitin supplement and the lack of reliable information about their usefulness in treating osteoarthritis,^[6] the National Institutes of Health funded a study 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.^[7] The control group of patients who took celecoxib (an osteoarthritis drug marketed by Pfizer) did have a statistically significant improvement in their symptoms. These results indicate that glucosamine and chondroitin do not effectively relieve osteoarthiritic pain. Although the study found no overall effect for the supplements, a secondary analysis of a subgroup of patients suggested that the supplements taken together helped people with more severe pain.

References

1. ^ P. A. Levene and F. B. La Forge (1913). "ON CHONDROITIN SULPHURIC ACID". J. Biol. Chem. 15: 69–79. Free PDF online
2. ^ Davidson EA, Meyer K (1954). "Chondroitin, a new mucopolysaccharide". J Biol Chem 211 (2): 605–11. PMID 13221568. Free PDF online
3. ^ ^a b Barnhill JG, Fye CL, Williams DW, Reda DJ, Harris CL, Clegg DO (2006). "Chondroitin product selection for the glucosamine/chondroitin arthritis intervention trial". J Am Pharm Assoc (Wash DC) 46 (1): 14–24. PMID 16529337.
4. ^ Silbert JE, Sugumaran G (2002). "Biosynthesis of chondroitin/dermatan sulfate". IUBMB Life 54 (4): 177–86. PMID 12512856.
5. ^ Adebowale AO Cox DS, Liang Z, Eddington ND (2000). "Analysis of glucosamine and chondroitin sulfate content in marketed products and the Caco-2 permeability of chondroitin sulfate raw materials". J Am Nutr Assoc 3: 37–44.
6. ^ McAlindon TE, LaValley MP, Gulin JP, Felson DT (2000). "Glucosamine and Chondroitin for Treatment of Osteoarthritis: A Systematic Quality Assessment and Meta-analysis". JAMA 283: 1469–1475. PMID 10732937.
7. ^ Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, Bradley JD, Bingham CO 3rd, Weisman MH, Jackson CG, Lane NE, Cush JJ, Moreland LW, Schumacher HR Jr, Oddis CV, Wolfe F, Molitor JA, Yocum DE, Schnitzer TJ, Furst DE, Sawitzke AD, Shi H, Brandt KD, Moskowitz RW, Williams HJ (2006). "Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis". New Engl J Med 354 (8): 795–808. PMID 16495392.

External links

• "Product Review: Joint Supplements (Glucosamine, Chondroitin, and MSM)" Summary of a Consumer Labs test of the actual composition of these supplements.

• "Glucosamine/Chondroitin Products Not Measuring Up", WebMD.com news report of the analysis of commercial supplements by Adebowale et al.

• "Chondroitin Sulfate Manufacturing and Risk of Mad Cow Disease" by Winston Wicomb, Ph.D., September 24, 2002. Information on methods for extraction of chondrotin sulfate from cow trachea, at the Stone Clinic of San Francisco.

• "Testing Status: CHONDROITIN SULFATE M030009", A thorough review of available information on the use of chondroitin sulfate in humans from the National Toxicology Program.

• Chondroitin Sulfate, summary of information on the use of chondroitin sulfate from the publishers of the Physicians' Desk Reference.

• "Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)," ClinicalTrials.gov information on the purpose, design, and analysis of the study.

• "NIH News: Efficacy of Glucosamine and Chondroitin Sulfate May Depend on Level of Osteoarthritis Pain", Wednesday, February 22, 2006.