Glucosamine & Chondroitin Sulfate-Containing Nutraceuticals: Potential Effects on Symptoms & Pathophysiologic Events in Osteoarthritis in Horses
ACVIM 2008
J.P. Caron
East Lansing, MI, USA


Osteoarthritis (OA) is characterized by the degeneration of articular cartilage accompanied with an excess production of inflammatory mediators the most noteworthy of which is the proinflammatory cytokine interleukin-1β. Widely accepted as one of the cytokines that plays a pivotal role in the pathophysiology of OA, it induces a cascade of catabolic events in chondrocytes including the up-regulation of genes coding for cartilage degrading enzymes such as aggrecanases and matrix metalloproteinases (MMPs). In addition to cartilage-degrading enzymes, it also induces the synthesis of other inflammatory molecules (such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase (mPGEs1)). Their activity leads to the release of prodigious quantities of the well-known inflammatory markers nitric oxide (NO) and prostaglandin E2 (PGE2), the latter of which is largely responsible for symptoms of the disease. Interleukin-1β also retards anabolic activities of the cartilage chondrocytes leading to declines in cartilage matrix synthesis (i.e., proteoglycans and collagen), thereby impairing any repair response. Other cytokines, such as tumor necrosis factor α, also contribute to the disproportionate production of these mediators and proteinases. Treatment goals for OA include reducing the severity of symptoms and attempting to impede the synthesis or activity of these harmful enzymes and mediators, so-called chondroprotective or disease-modifying effects.

While there are a number of nutraceutical products used for the treatment of OA and their number is growing rapidly, the most common constituents, used alone or in combination, are glucosamine (GLN) and chondroitin sulfate (CS). Both GLN and CS have negligible toxic effects and it is increasingly evident that they possess disease-modifying and, at least some, symptomatic effects in osteoarthritis (OA). Because of their relative safety compared to other treatment options and their ease of administration, they could play an important role in joint disease treatment even if they are only moderately effective for the treatment of symptoms.


GLN is an aminomonosaccharide and a major building block of cartilage proteoglycans. GLN is most commonly included in feed supplements as either the hydrochloride or sulfate salt, which appear to have similar biologic effects in vitro, although some maintain the sulfate form is superior with respect to clinical efficacy.Clinical trials show that GLN administered orally is effective in decreasing pain and improving joint mobility in osteoarthritis (OA) patients. Recent experiments have shown that glucosamine is capable of reducing the synthesis of degradative enzymes and does so by inhibiting the expression of the genes coding for these proteins and other inflammatory mediators in cartilage cultures in a number of species, including horses.

Chondroitin Sulfate

CS, a complex glycosaminoglycan, is a major component of aggrecan. It resembles polysulfated glycosaminoglycan (PSGAG--Adequan®) in structure and, although substantially less richly sulfated, its mechanisms of action are thought to be rather similar. Purported beneficial effects include improvement in joint mobility, joint space narrowing and a reduction of erosive OA lesions. CS also has protective effects for cartilage proteoglycan loss in animal models of joint inflammation. Experiments using cultured chondrocytes have provided evidence of chondroprotective effects of chondroitin sulfate including stimulating the synthesis of proteoglycans and inhibiting the activity of certain matrix degrading enzymes.

Glucosamine and chondroitin sulfate: GLN is commonly combined with CS in many of the commercially available nutraceutical products. The combination is thought to be effective in reducing pain, improving joint function, halting or reversing joint degeneration in humans with mild to moderate OA of the knee; effects observed with each given individually but improved when GLN and CS are combined. Severe cartilage lesions in laboratory animal models of OA are also reduced with GLN and CS in combination. To date, there have been few in vitro studies aimed at determining the mode of action of GLN and CS in combination.

Mechanism(s) of Action

Despite several studies with positive results, the exact mechanism of action of these nutraceuticals still remains to be resolved. Metabolic effects appear to be multi-faceted and complex, which has accounted for our lack of clear understanding of their precise actions. Symptomatic relief with GLN and CS may be attributed to a reduction in inflammatory mediators, in particular PGE2. In vitro, cytokine-stressed cartilage explants treated with GLN demonstrate a decline in gene expression of a variety of the aforementioned enzymes and mediators. For example, treatment of stimulated explants with GLN reduces iNOS transcript and NO release into the media as well as effecting reductions in aggrecanase and a variety of MMPs including MMP 1 and MMP 13. These events are paralleled by the inhibition of COX-2 and PGE2 production and release. Similar though not identical results are observed with CS treatment. Importantly, the combination of GLN and CS does not only reduce the expression of destructive molecules, it has been shown that the combination can result in induction of natural anti-inflammatory molecules such as the tissue inhibitors of matrix metalloproteinases (TIMP).1 These effects are likely a result of regulation of the nuclear factor kappa beta (NFκB) and the mitogen-activated protein kinase (MAPK) pathways.

Bioavailability and Applicability of In vitro Studies

The applicability of many in vitro mechanistic studies is limited by concentrations of nutraceuticals used that greatly exceed those generally found in blood and synovial fluid. The concentrations of GLN in blood and synovial fluid after oral and intravenous administration range from about 0.05 to 20 μg/ml.2-4 Depending on the route of administration, species, and the source and molecular weight of CS, the concentration of CS in serum ranges from 5 to 200 μg/ml.3,5 In past studies, cartilage explant cultures or cell cultures stimulated with IL-1 demonstrated suppression of NO and PGE2 release to the media with supplementation of GLN and CS in the concentration range of 0.1 to 10 mg/ml. Two other studies employed concentrations of GLN and CS that are likely attainable in vivo and have shown that these nutraceuticals were able to prevent a decline in proteoglycan synthesis with catabolic agents. Recently, we published our results on the ability of biologically relevant concentrations of GLN (5 μg/ml) and CS (20 μg/ml) to regulate expression of iNOS, COX-2 and mPGEs1 genes accompanied by reductions in IL-1 induced release of NO and PGE2.6 These concentrations of GLN and CS were also able to repress major cartilage proteolytic enzymes implicated in OA pathogenesis at the pre-translational level. Thus, while recent investigations by the group at the Université de Montréal have shown that the amount of glucosamine available after oral dosing at currently recommended doses in horses is indeed modest,2 data from our laboratories supports significant favorable effects on gene expression at very low concentrations.1,6,7 Realizing these goals under clinical conditions requires the administration of adequate quantities--this requires using products of certified quality and content (which can vary widely)8 and may entail exceeding currently recommended doses.

Clinical Results

High quality research on the clinical effects of nutraceuticals is very limited, however a recent well-designed study examining clinical effects in veteran horses provided encouraging results.9 Specifically, the results of this study revealed that treated (GLN and CS) horses had improved stride length, joint range of motion and other indices of lameness compared to control animals. Interestingly, as has been observed in people, results were not apparent until the second month of supplementation.


From the above, it appears that GLN and CS are capable of modulating pathophysiologic events of OA and do so at concentrations approaching those achieved by oral administration at recommended levels in horses. There are also some data indicating clinical improvements in affected horses, indicating that they indeed have some symptomatic efficacy. Nonetheless, their effects on lameness are not nearly as potent as those associated with corticosteroid and NSAID therapies.

The type and severity of OA lesions that can be expected to respond to the administration of oral supplements containing GLN and/or CS remains to be determined. It may well be that GLN and CS-containing nutraceuticals will find greater use in prevention rather than in therapy of existing disease and it is likely that greater benefits will be realized when GLN and CS are used in combination. It is recommended to use products providing certified content from reputable sources.


1.  Chan PS, Caron JP, Orth MW. Short-term gene expression changes in cartilage explants stimulated with interleukin-1 beta plus glucosamine and chondroitin sulfate. J Rheumatol 33:1329-40, 2006.

2.  Laverty S, Sandy JD, Celeste C, et al. Synovial fluid levels and serum pharmacokinetics in a large animal model following treatment with oral glucosamine at clinically relevant doses. Arthritis Rheum 52:181-91, 2005.

3.  Du J, White N, Eddington ND. The bioavailability and pharmacokinetics of glucosamine hydrochloride and chondroitin sulfate after oral and intravenous single dose administration in the horse. Biopharm Drug Dispos 25:109-16, 2004.

4.  Setnikar I, Palumbo R, Canali S, Zanolo G. Pharmacokinetics of glucosamine in man. Arzneimittelforschung 43:1109-13, 1993.

5.  Du J, Eddington N. Determination of the chondroitin sulfate disaccharides in dog and horse plasma by HPLC using chondroitinase digestion, precolumn derivatization, and fluorescence detection. Anal Biochem 306:252-8, 2002.

6.  Chan PS, Caron JP, Orth MW. Glucosamine and chondroitin sulfate regulate gene expression and synthesis of nitric oxide and prostaglandin E2 in articular cartilage explants. Osteoarthritis Cartilage 13:387-94, 2005.

7.  Chan PS, Caron JP, Orth MW. The effects of glucosamine and chondroitin sulfate on bovine cartilage explants under long-term culture conditions. Am J Vet Res 68; 709-16, 2007.

8.  Oke S, Aghazadeh-Habashi A, Weese JS, Jamali F. Evaluation of glucosamine levels in commercial equine oral supplements for joints. Equine Vet J 38:93-5, 2006.

9.  Forsyth RK, Brigden CV, Northrop AJ. Double blind investigation of the effects of oral supplementation of combined glucosamine hydrochloride and chondroitin sulphate on stride characteristics of veteran horses. Equine Vet J (Suppl) 36:622-5, 2006.

Speaker Information
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J. Caron
Michigan State University
East Lansing, MI

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