Chondroitin 4-Sulfate: From Osteoarthritis Research to Immunomodulatory Roles and Safety Considerations

Chondroitin 4-sulfate has been studied for the treatment of arthritis; however, information on its effectiveness is conflicting. It is commonly given in combination with other agents, such as glucosamine sulfate or glucosamine hydrochloride. It has also been studied for use in drug delivery, antithrombotic and extravasation therapy, treatment of dry eyes, and cystitis. Chondroitin sulfate is a high-viscosity, anionic mucopolysaccharide (glycosaminoglycan) with N-acetylchondrosine as a repeating unit and one sulfate group per disaccharide unit. Chondroitin 4-sulfate and chondroitin 6-sulfate are the most abundant mucopolysaccharides and occur in skeletal and soft connective tissue. Chondroitin's molecular weight is about 50,000, depending on product source or preparation.

Chondroitin Sulfate Supplements for Osteoarthritis

Osteoarthritis (OA) is a common condition that causes serious disability. OA affects approximately 3.5% of the global population. OA affects synovial joints, which are made of a capsule lined by the synovium and cartilage that covers bone ends. Cartilage is composed of water, chondrocytes, collagen, and proteoglycans. Chondroitin 4-sulfate (CS) is a natural glycosaminoglycan and is found in all connective tissues, especially in the extracellular matrix (ECM) of articular cartilage. This sulfate is covalently attached to a sugar composed of glucuronic acid (GlcA) and N-acetylgalactosamine (GalNAc). CS possesses a negative charge, interacts with proteins in the ECM, and helps regulate many cellular processes. Chondroitin 4-sulfate is extracted from animal sources and submitted to purification processes for commercial use. Due to different purification processes, the presence of bacteria, viruses, or prions cannot be excluded. Additionally, various other natural contaminants may be present in CS products. More recently, investigations have focused on the anti-inflammatory properties of CS. In one recent study, Chondroitin 4-sulfate induced the epithelial-mesenchymal transition, increased the expression of type II collagen and tissue inhibitors of metalloproteinases -1 and -2, and inhibited the expression and activity of metalloproteinase-9 and metalloproteinase-2. The phosphorylation of Akt, IκB kinase (IKK), IκB, and p65 was decreased by Chondroitin 4-sulfate.[1]

More recently, CS has been trialed as a delivery mechanism for other substances into the cartilage. This type of combination therapy may be important in delaying the progression of OA. In some animal studies, promising results have been achieved in this regard. In conclusion, the investigation of Chondroitin 4-sulfate use for the treatment of OA is still ongoing. This review offers insight into many of its therapeutic effects and current trials on the topic; however, study methodology flaws and lesser-quality products may have limited reaching definitive conclusions on this matter in the past. The concurrent use of glucosamine sulfate and chondroitin sulfate in many of these trials may have also limited the differentiation of the isolated benefit of Chondroitin 4-sulfate. In the future, further investigation should strive to use CS supplements of pharmacologic grade that have been properly subjected to rigorous purification methods and quality control. Study protocols should also be properly standardized, with well-designed randomized controlled trials and a longer-term follow-up that is needed to derive benefit from this slow-acting drug. Newer studies should also strive to use Chondroitin 4-sulfate supplements as monotherapy, avoiding combinations with other SYSADOAs such as glucosamine.

Effectiveness and safety of Chondroitin 4-sulfate

In recent years, there has been a fierce controversy over the efficacy of glucosamine, Chondroitin 4-sulfate, or the two in combination in the treatment of knee osteoarthritis (OA). The recommendations given by the American College of Rheumatology conditionally do not advocate the use of glucosamine and chondroitin in the treatment of knee OA. The clinical practice guideline of American Academy of Orthopaedic Surgeons also provides strong evidence that the use of glucosamine and Chondroitin 4-sulfate cannot be recommended. Similarly, the 2014 Osteoarthritis Research Society International (OARSI) guidelines conditionally do not recommend the use of them. v For the present study, the combination of direct and indirect evidences is an effective way to enhance estimate accuracy, as it can narrow the width of Chondroitin 4-sulfate interval compared to direct estimate alone. On the basis of existing evidences, this study conducted a network meta-analysis of RCTs to examine the safety and efficacy of glucosamine, chondroitin, the combination of the two, or celecoxib in the control of knee OA. This network meta-analysis included 54 studies covering 16,427 knee OA patients. The results indicated significant effects of glucosamine plus chondroitin in pain relief and function improvement compared to the placebo group.[2]

To our best knowledge, this is the first network meta-analysis that compares glucosamine, Chondroitin 4-sulfate, and the two in combination with celecoxib or placebo for the treatment of knee OA. Both direct and indirect comparisons were taken into account while fully preserving randomization. The evidence provided by this study could support the conclusion of the latest RCT that glucosamine and Chondroitin 4-sulfate have comparable efficacy over celecoxib in pain relief and function improvement. In view of the limited number of direct evidences that compare glucosamine plus Chondroitin 4-sulfate with others options, further high-quality RCTs involving direct comparisons, particularly industrial independent trails that examine the structure-modifying effects, are desired. Some additional questions should be addressed as well, e.g., what is the best treatment duration (shortest in the case of effective). Moreover, the follow-up duration of future studies should be extended to determine whether the treatment effects may diminish with time. Apart from these areas, there is a particularly important suggestion with respect to the target population. Subsequent RCTs need to test the effect of the combination of glucosamine and chondroitin on knee OA patients with moderate-to-severe pain.

Immunomodulatory and anti-inflammatory effects of Chondroitin 4-sulfate

Chondroitin sulphate (CS) is a natural glycosaminoglycan (GAG) present in the extracellular matrix surrounding cells, especially in the cartilage, skin, blood vessels, ligaments and tendons, where it forms an essential component of proteoglycans (PG). Chondroitin 4-sulfate is the main disaccharide unit of cartilage GAG, formed by the 1–3 linkage of D-glucuronic acid to N-acetylgalactosamine. The disaccharide units are attached by β 1–4 galactosamine links. The galactosamine residues are sulphated either in position 4 (Δdi-4S), 6 (Δdi-6S) or 4 and 6 (Δdi-4,6S). The sulphate groups along with the carboxyl groups of glucuronic acid are ionized, conferring a negative charge. In the extracellular matrix of the cartilage, about 100 chains of CS, each containing 50 to 60 disaccharide units, are covalently attached to a long polypeptide backbone composed of more than 2000 amino acids. Because Chondroitin 4-sulfate elicits a key role in the articulation, many research groups have focused on the role of CS on the chondrocytes, the synovial membrane and the subchondral bone. In human subchondral bone osteoblasts, CS up-regulates osteoprotegerin (OPG) expression and decreases RANKL expression; as a consequence, Chondroitin 4-sulfate increases the ratio of OPG/RANKL.[3]

Despite the limitations of the in vitro and in vivo animal models because of differences in Chondroitin 4-sulfate dosages, routes of administration and duration of exposure, this review supports that by inhibiting nuclear translocation of NF-κB and subsequent production of pro-inflammatory cytokines, and COX-2 and PLA2 expression and activity, CS might potentially be of interest for the treatment of many inflammatory and autoimmune diseases, besides OA. Being CS a SYSADOA, we predict that an effect of Chondroitin 4-sulfate could only be detected on long-term treatments, for example months. Because of the nature, the evolution and the difficulty to treat the inflammatory or autoimmune diseases, animal and human studies are warranted to test whether CS provides any beneficial effect.

References

[1]Brito R, Costa D, Dias C, Cruz P, Barros P. Chondroitin Sulfate Supplements for Osteoarthritis: A Critical Review. Cureus. 2023 Jun 9;15(6):e40192. doi: 10.7759/cureus.40192. PMID: 37431333; PMCID: PMC10329866.

[2]Zeng C, Wei J, Li H, Wang YL, Xie DX, Yang T, Gao SG, Li YS, Luo W, Lei GH. Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee. Sci Rep. 2015 Nov 18;5:16827. doi: 10.1038/srep16827. PMID: 26576862; PMCID: PMC4649492.

[3]du Souich P, García AG, Vergés J, Montell E. Immunomodulatory and anti-inflammatory effects of chondroitin sulphate. J Cell Mol Med. 2009 Aug;13(8A):1451-63. doi: 10.1111/j.1582-4934.2009.00826.x. Epub 2009 Jun 11. PMID: 19522843; PMCID: PMC3828858.