Chondroitin sulfate
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Product Description
Chondroitin sulfate (CS) is a naturally occurring glycosaminoglycan composed of alternating N-acetyl-β-d-galactosamine and β-d-glucuronic acid units that can carry 4-O- and/or 6-O-sulfate groups in patterns that dictate its biological activity. A major structural element of cartilage and other connective tissues, CS is best known as an over-the-counter dietary supplement (and an EMA-approved prescription drug in Europe) paired with glucosamine to relieve pain and improve mobility in knee and hip osteoarthritis; mounting evidence also suggests it may slow cartilage breakdown, earning it the label of a symptomatic slow-acting drug for osteoarthritis (SYSADOA). Beyond joints, recent work shows that the sulfation “code” of CS fine-tunes its roles in health and disease: in the eye, vitreous samples from patients with rhegmatogenous retinal detachment contain unusually high amounts of under-sulfated CS domains that weaken the gel’s collagen network, implying that CS sulfation patterns help maintain vitreous stability.
Synthesis and Production
1. Biosynthesis (Endogenous)
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Process: Chondroitin sulfate (CS) is naturally synthesized in the endoplasmic reticulum (ER) and Golgi apparatus of cells.
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Key Steps:
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Initiation: Xylosyltransferase attaches a xylose sugar to a serine residue on a core protein (e.g., versteam or type IX collagen), forming a proteoglycan.
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Chain Elongation: Chondroitin synthase alternately adds D-glucuronic acid (GlcA) and N-acetylgalactosamine (GalNAc) from UDP-sugar donors to form the polysaccharide chain.
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Sulfation: Specific sulfotransferases, such as chondroitin 4-O-sulfotransferase and 6-O-sulfotransferase, add sulfate groups to the GalNAc residues, defining the CS type (e.g., CS-A, CS-C, CS-E).
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2. Commercial Production (Exogenous)
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Primary Sources: Extracted predominantly from animal tissues, including:
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Marine Sources: Shark, whale, ray, and tilapia cartilage (often preferred for specific sulfation patterns).
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Terrestrial Sources: Bovine, porcine, and buffalo cartilage and tissues.
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Extraction and Purification Methods:
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Delipidation: Removal of fats using organic solvents like chloroform, acetone, or ethanol.
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Proteolytic Digestion: Enzymatic breakdown of proteins using papain, trypsin, or alcalase to release CS from the tissue matrix.
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Purification: Involves techniques such as:
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Precipitation with alcoholic solvents (methanol, ethanol).
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Ultrafiltration-diafiltration (UF-DF).
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Ion-exchange chromatography (IEC) and gel filtration chromatography.
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Dialysis and lyophilization (freeze-drying).
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Synthetic and Semi-Synthetic Methods:
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Enzymatic Synthesis: Using engineered enzymes (e.g., chondroitin synthase and sulfotransferases) to polymerize and sulfate the chain in a controlled manner. For example, CS-E can be produced by sulfating CS-A with GalNAc4S-6OST.
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Chemical/Semi-Synthesis: Chemically modifying naturally derived CS using sulfating agents (e.g., trimethylamine sulfur trioxide) to create specific sulfation patterns.
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Microbial Synthesis: Using genetically engineered microorganisms (e.g., E. coli) in fermentation processes to produce CS, offering a potential sustainable and animal-free alternative.
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Uses and Applications
1. Pharmaceutical and Therapeutic
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Osteoarthritis Treatment: A widely used symptomatic slow-acting drug (SYSADOA). It provides pain relief, improves joint mobility, and may slow disease progression by:
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Modulating inflammatory and catabolic factors (inhibiting nitric oxide synthase, COX-2, prostaglandin E2, and MMPs).
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Stimulating the synthesis of hyaluronate, type II collagen, and proteoglycans.
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Cartilage Tissue Engineering: Incorporated into 3D scaffolds, hydrogels, and nanofibers to promote chondrocyte proliferation, differentiation, and extracellular matrix (ECM) synthesis for repairing joint injuries and degeneration.
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Novel Drug Delivery Systems: Used in nanoparticles, microcapsules, and films for sustained and targeted drug release, leveraging its biocompatibility and polyelectrolyte nature.
2. Nutraceutical and Animal Feed
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Human Dietary Supplements: Marketed for joint health, often in combination with glucosamine.
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Animal Nutrition:
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Broiler Chickens: Supplementation (0.06–0.12%) improves bone quality, calcium content, breaking strength, and reduces mortality.
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Weaned Piglets: Combined with 25-hydroxyvitamin D3 and glucosamine sulfate, it enhances growth performance, calcium/phosphorus metabolism, and bone mineral density.
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3. Cosmetic and Personal Care
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Functions: Used as an antistatic and hair conditioning agent in cosmetic products due to its hydrating and film-forming properties.
4. Other Applications
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Biomedical Research: Studied for roles in wound repair, central nervous system function, and as a pathogen receptor.
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Biomaterial: Its properties are exploited in various hydrogels and bio-inks for regenerative medicine.
Chemical and Physical Properties
1. Chemical Structure
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Composition: An anionic glycosaminoglycan (GAG) composed of repeating disaccharide units of D-glucuronic acid and N-acetylgalactosamine.
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Sulfation: The pattern of sulfate groups (at the 4-O and/or 6-O position of GalNAc) defines its subtypes (CS-A, CS-C, CS-D, CS-E) and biological activity.
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Molecular Formula: C₁₃H₂₁NO₁₅S (for a representative disaccharide unit).
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Molecular Weight: ~463.37 g/mol (for a disaccharide unit); commercial CS is a polymer with a wide molecular weight range (e.g., 10-100 kDa).
2. Physicochemical Properties
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Polyelectrolyte Nature: Highly negative charge due to sulfate and carboxylate groups, enabling strong interactions with cations, proteins, and growth factors.
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Hydrophilicity: Excellent water-binding capacity, absorbing up to 1000 times its dry volume, which contributes to its role in providing swelling pressure and resilience in tissues.
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Biocompatibility and Biodegradability: Naturally occurring in the body, it is well-tolerated and can be broken down by enzymes like chondroitinase.
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Computational Properties:
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XLogP3: -4.8 (indicating high hydrophilicity).
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Hydrogen Bond Donor/Acceptor Count: 8 and 15, respectively.
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Topological Polar Surface Area (TPSA): 267 Ų.
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3. Functional Characteristics
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ECM Interaction: Crucial for maintaining the structural organization of the extracellular matrix. It stabilizes collagen fibrils (e.g., via type IX collagen) and interacts with other matrix components.
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Biological Signaling: Binds to and modulates the activity of growth factors, cytokines, and other signaling molecules, influencing cell behavior, morphogenesis, and inflammation.
Safety and Handling
1. Hazard Identification (Based on PubChem GHS Data)
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Classification: A minority of safety reports classify it with the following hazards:
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H317: May cause an allergic skin reaction (Skin Sensitization 1).
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H332: Harmful if inhaled (Acute Toxicity 4, Inhalation).
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H334: May cause allergy or asthma symptoms or breathing difficulties if inhaled (Respiratory Sensitization 1).
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Signal Word: Danger (based on the above classifications).
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Pictograms: GHS07 (Exclamation mark) and GHS08 (Health hazard).
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Note: The majority of safety reports (63.6%) indicate that it does not meet GHS hazard criteria.
2. Safety Profile
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General Use: Considered safe for consumption as a dietary supplement and for use in cosmetics and pharmaceuticals.
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Pharmacology: When taken orally, it is absorbed from the gastrointestinal tract with a bioavailability of 10-20%. It has a low protein binding (0.23%) and an elimination half-life of approximately 15 hours. It is not metabolized by cytochrome P450 enzymes.
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Experimental Properties:
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Melting Point: 190–194 °C.
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Solubility: Soluble in water.
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3. Regulatory Information
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Drug Status: A prescription drug in Europe and an over-the-counter (OTC) dietary supplement in North America.
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ATC Code: M01AX25 (Antiinflammatory and antirheumatic products, non-steroids).
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Regulatory Approvals: Listed in various national inventories (e.g., EPA TSCA, Australian AICIS, New Zealand EPA), often with exemptions or approvals for use under specific standards.