INTRODUCTION
Osteoarthritis, or degenerative joint disease, is caused by the breakdown of cartilage. Cartilage is the connective tissue that cushions the ends of bones within the joint. It is characterized by pain, joint damage, and limited motion. The disease generally occurs late in life, and most commonly affects the hands and large weight-bearing joints. Although the disease can impact several joints, the knees are often affected. Age, female gender, and obesity are risk factors for this condition.
Chondroitin sulphate has been found to be a major component for proteoglycans. Proteoglycans are glycoproteins in the extracellular matrix. Among proteoglycans, the most abundant type is the hyalectan or lectican family. Proteoglycans are formed by two main components; a protein and a sugar chain, which that is termed glycosaminoglycan. These glycosaminoglycans are polymers of two simple sugars. The hyalectan family has glycosaminoglycans of the chondroitin sulphate type, and they are termed proteoglycans-chondroitin sulphate.
Glucosamine and chondroitin are natural substances found in and around the cells of cartilage. These substances may help in the repair and maintenance of cartilage. Here is the key difference in their functions: glucosamine inhibits inflammation and stimulates cartilage cell growth, while chondroitin provides cartilage with strength and resilience. But, glucosamine and chondroitin are classified as dietary supplements.
CHONDROITIN SULFATE AS A SYMPTOMATIC SLOW-ACTING DRUG AND AS A SUPPLEMENT
Chondroitin sulfate is considered as a symptomatic slow-acting drug, i.e. a compound that has a slow onset of action and improve osteoarthritis symptoms after a couple of weeks. Chondroitin sulfate exhibits a wide range of biological activities and from a pharmacological point of view it produces a slow but gradual decrease of the clinical symptoms of osteoarthritis and these benefits last for a long period after the end of treatment. Many research articles show that chondroitin sulfate could have an anti-inflammatory activity and a chondroprotective action by modifying the structure of cartilage. These properties are also related to the oral adsorption of this molecule as high-molecular mass compounds having clusters of sulfate groups and high charge density capable of exert their chondroprotective activity in vivo. However, all the conclusive studies with chondroitin sulfate resulted from the use of experimental dosage designs, which may different from commercially available supplements. [3,4] The oral absorption for an experimental chondroitin sulfate formulation is 70%. [2]
POTENTIAL HEALTH BENEFITS OF CHONDROITIN
BONE - Chondroitin sulfates play a role in articular and bone metabolism by controlling cartilaginous matrix integrity and bone mineralization. Chondroitin sulfates are synthesized in chondrocytes and in bone cells. Binding to the core protein through N- and O-linkages leads to aggregates of monomers with high molecular weights. The proteoglycan aggregate exhibits viscoelastic and hydration properties and an ability to interact with the surrounding tissue through electric charges leading to protection of the cartilaginous tissues. Chondroitin sulfates inhibit the activity of extracellular proteases for the connective tissues. In addition to their anti-inflammatory effects, chondroitin sulfates in vitro stimulate proteoglycan production by chondrocytes; they also inhibit cartilage cytokine production and induce apoptosis of articular chondrocytes. [14, 15]
Chondroitin sulfates increase the intrinsic viscosity of the synovial liquid. In vivo in experimental arthritis, the number and severity of articular symptoms decreases after chondroitin sulfates administration. In bones, chondroitin sulfates accelerate the mineralization process and bone repair. However, they break down easily via enzymatic degradation ( metalloproteinases and lysosomal enzymes). [14]
A study investigated how chondroitin sulfate might help with osteoporosis caused by calcium deficiency. The researchers created rats with osteoporosis by giving them a low-calcium diet. Adding calcium carbonate (common calcium supplement) helped bone health. Interestingly, giving the rats chondroitin sulfate alongside the low-calcium diet also improved bone mineral density. And, the study also suggests chondroitin sulfate affects gut bacteria in a way that promotes calcium absorption and reduces inflammation, both helpful for bones. This is a good first step, but further studies are needed to confirm these findings in humans before recommending chondroitin sulfate for osteoporosis. Overall, the study provides evidence that chondroitin sulfate could be a potential dietary supplement to help with osteoporosis caused by calcium deficiency. [A4]
NEURAL SYSTEM - Proteoglycans-chondroitin sulphates are linked to the hyaluronic acid and other molecules of the extracellular matrix in order to form a three-dimensional network. This network has several important roles in the maintenance of the homeostasis of the central nervous system. [8-12]
Carulli D and co-workers from Cambridge University considered the possible benefits of chondroitin sulfate on nerve cell regeneration. As described before, proteoglycans are of two main types, chondroitin sulfate and heparin sulfate. The chondroitin sulfate acts mainly as barrier-forming molecules, whereas the heparin sulfate stabilise the interactions of receptors and ligands. During development chondroitin sulfates pattern cell migration, axon growth pathways and axon terminations. Later in development and in adulthood chondroitin sulfates associate with some classes of neuron and control plasticity. After damage to the nervous system, chondroitin sulfates are the major axon growth inhibitory component of the glial scar tissue that blocks successful regeneration.
Chondroitin sulfates have a variety of roles in the nervous system, including binding to molecules and blocking their action, presenting molecules to cells and axons, localising active molecules to particular sites and presenting growth factors to their receptors. [1, 13]
CANCER - Some researchers are interested in chondroitin's role in tumor cell invasion and metastasis. [14] Tumor cell invasion and metastasis is highly dependent on dynamic changes in the adhesion and migration of transformed and malignant cells. As with normal cell adhesion, the adhesion of tumor cells influences their cytoskeletal organization, activation of signal transduction pathways within the cell, and nuclear events leading to changes in mRNA transcription and protein synthesis. Furthermore, as tumor cells invade the circulation, they adhere to activated endothelial cells at sites within the vasculature during arrest and extravasation.
Studies in the area of tumor cell adhesion and migration have demonstrated that the recognition of extracellular matrix ligands, or adhesion promoting ligands expressed on neighboring cells (i.e. counter-receptors), involves complex molecular recognition mechanisms. The complexity arises, in part, from the multiple recognition sites that are present within adhesion promoting ligands. Some of these structures within ECM components act by binding integrins, whereas others bind additional receptors such as cell surface proteoglycans. In this sense, adhesion promoting ligands may be considered as informational arrays, that function to modulate cell phenotype by engaging specific combinations of adhesion receptors on the cell surface. Thus, cell surface chondroitin sulfate proteoglycans may play in modulating tumor cell adhesion, migration and invasion.
Epidemiologic studies have reported inverse associations of non-steroidal anti-inflammatory drug (NSAID) use and lung cancer risk. Brasky TM et al at The Fred Hutchinson Cancer Research Center, Seattle, found that ever use of glucosamine and chondroitin, which have anti-inflammatory properties, were inversely associated with lung cancer risk. They run a survey and further proved the observation. Their results for glucosamine use are similar to the prior human studies of NSAID use and lung cancer, both in magnitude and the limitation of the association to adenocarcinoma. Unlike NSAIDs, glucosamine has no known adverse effects or serious side effects. [A1]
On the other hand, Renate Pichler and colleagues argue that Bacillus Calmette-Guérin treatment for bladder cancer can be a double-edged sword. While it helps fight the cancer cells, it can also trigger inflammation in the bladder lining, leading to painful symptoms like frequent urination, urgency, and incontinence. This inflammation happens because a protective layer in the bladder breaks down, allowing irritants to reach the tissue. They are looking for ways to heal this damaged layer. They're exploring treatments using substances called chondroitin and hyaluronic acid, which could help rebuild the protective barrier and reduce bladder irritation caused by BCG. In a small study, these substances seemed to be effective in relieving symptoms in some patients. [A3]
However, Brasky TM et al at Fred Hutchinson Cancer Research Center did not found any benefit of chondroitin on prostate cancer from a survey of 35,239 male. [A2]
SIDE EFFECTS OF CHONDROITIN
Glucosamine and chondroitin sulphate are naturally occurring substances. Both substances can be taken by mouth and have no known significant toxicity nor side effects. Glucosamine and chondroitin sulphate have been examined in laboratory and animal experiments, and in several clinical studies, which have shown some effect on the symptoms of early or moderate arthritis. The long-term effect has not been evaluated sufficiently and studies of the relation between dose and effect are lacking for both compounds. [5,6]
REFERENCE
[1] Carulli D et al, Chondroitin sulfate proteoglycans in neural development and regeneration. Curr Opin Neurobiol. 2005 Apr;15(2):252. [2] Owens S Recent advances in glucosamine and chondroitin supplementation. J Knee Surg. 2004 Oct;17(4):185-93. [3] Volpi N The pathobiology of osteoarthritis and the rationale for using the chondroitin sulfate for its treatment. Curr Drug Targets Immune Endocr Metabol Disord. Jun;4(2):119-27.2004. [4] Reginster JY et al, Naturocetic (glucosamine and chondroitin sulfate) compounds as structure-modifying drugs in the treatment of osteoarthritis. Curr Opin Rheumatol. 2003 Sep;15(5):651-5. [5] Angermann P Glucosamine and chondroitin sulfate in the treatment of arthritis Ugeskr Laeger. 2003 Jan 27;165(5):451-4. [6] Bijlsma JW Glucosamine and chondroitin sulfate as a possible treatment for osteoarthritis Ned Tijdschr Geneeskd. 2002 Sep 28;146(39):1819-23. [7] Brief AA et al, Use of glucosamine and chondroitin sulfate in the management of osteoarthritis. J Am Acad Orthop Surg. 2001 Mar-Apr;9(2):71-8. [8] Crespo-Santiago D et al, The extracellular matrix of the central nervous system: chondroitin sulphate type proteoglycans and neural repair Rev Neurol. 2004 May 1-15;38(9):843-51. [9]Grumet M et al, Functions of brain chondroitin sulfate proteoglycans during developments: interactions with adhesion molecules. Perspect Dev Neurobiol. 1996;3(4):319-30. [10] Margolis RU et al, Chondroitin sulfate proteoglycans as mediators of axon growth and pathfinding. Cell Tissue Res. 1997 Nov;290(2):343-8. [11] Oohira A et al, Molecular interactions of neural chondroitin sulfate proteoglycans in the brain development. Arch Biochem Biophys. 2000 Feb 1;374(1):24-34. [12] Rauch U et al, Neurocan: a brain chondroitin sulfate proteoglycan. Cell Mol Life Sci. 2001 Nov;58(12-13):1842-56. [13] Zhuo L et al, A physiological function of serum proteoglycan bikunin: the chondroitin sulfate moiety plays a central role. Glycoconj J. 2002 May-Jun;19(4-5):241-7. [14] Bali JP et al, Biochemical basis of the pharmacologic action of chondroitin sulfates on the osteoarticular system. Semin Arthritis Rheum. 2001 Aug;31(1):58-68. [15] Kelly GS The role of glucosamine sulfate and chondroitin sulfates in the treatment of degenerative joint disease. Altern Med Rev. 1998 Feb;3(1):27-39. [16] Iida J et al, Cell surface chondroitin sulfate proteoglycans in tumor cell adhesion, motility and invasion. Semin Cancer Biol. 1996 Jun;7(3):155-62 A1. Cancer Causes Control. 2011 Sep;22(9):1333-42. A2. Nutr Cancer. 2011 May;63(4):573-82. A3. Renate Pichler et al, Treating BCG-Induced Cystitis with Combined Chondroitin and Hyaluronic Acid Instillations in Bladder Cancer, J Clin Med. 2024 Mar 31;13(7):2031. A4. Tianshu Liu et al, Chondroitin sulfate alleviates osteoporosis caused by calcium deficiency by regulating lipid metabolism, Nutr Metab (Lond). 2023 Feb 6;20(1):6.