page_title: Polysulfated glycosaminoglycan
section_title: Mechanism of action
hierarchical_section_title: Polysulfated glycosaminoglycan / Pharmacology / Mechanism of action
caption_attribution_description: English: GAGs, proteoglycan, glycoproteins, cartilage matrix
context_page_description: Polysulfated glycosaminoglycan, sold under the brand name Adequan, is an injectable drug for dogs and horses that is used to alleviate the lameness, pain, and lowered range of motion caused by arthritis. It is made of repeat disaccharide units, and is similar to glycosaminoglycans already present in the cartilage; PSAG thus easily integrates itself there. In vitro studies have shown it to inhibit the enzymes that degrade cartilage and bone, as well as suppress inflammation and stimulate the synthesis of replacement cartilage. While it can cause an increased risk of bleeding, its relatively safe and has a high LD50. PSAG is one of the most widely prescribed joint supplements for horses.
  While it is widely used, some studies still show conflicting results in terms of efficacy, causing some to claim that PSGAG is not solely responsible for the significant mitigation of arthritis seen in success cases.
context_section_description: Normally, joint cartilages have proteoglycan complexes, which are proteins with side chains made of glycosaminoglycans such as keratan sulfate and chondroitin sulfate attached to strands of hyaluronic acid. The glycosaminoglycan side chains are polyanionic, which causes adjacent side chains to push each other away and create a "bottle brush", where hyaluronic acid is the stem and the side chains are the bristles. When pressure is exerted on the joint, fluids move between the chondrocytes and synovial fluid, exchanging nutrients.
  In degenerative joint disease, the proteoglycan complexes start disappearing, and the hyaluronate becomes poorer in quality and scarcer. This lowers the viscosity of the synovial fluid (which increases friction) and causes white blood cells and enzymes to enter and effect cartilage degradation and inflammation. Steroids that are released as a result kill the chondrocytes. The remaining chondrocytes have trouble exchanging nutrients with the synovial fluid, which would allow them to repair some damages.
  The mechanism of PSGAG in vivo is based off observations and studies in vitro. PSGAG inhibits many of the catabolic enzymes that degrade cartilage, proteoglycans, and hyaluronic acid. The enzymes that are inhibited include serine proteases, which play a role in the IL-1 degradation of proteoglycans and collagen; lysosomal enzymes that cause proteoglycans to dissociate from hyaluronic acid; elastase; metalloproteinases such as stromelysin, which degrade cartilage matrix proteins; collagenases such as cathepsin B1; and hyaluronidase. PSGAG inhibits the synthesis of prostaglandin E2, which is released upon joint injury and causes inflammation, increases the loss of proteoglycan, and reduces the threshold of pain receptors. Inhibiting the complement pathway further reduces inflammation, most likely by altering C-reactive protein.  The inhibition of blood coagulation reduces resultant fibrinolysis, which would cause cell death and increase local inflammation.
  PSGAG also stimulates the synthesis of glycosaminoglycans, hyaluronic acid, and collagen, which increase synovial viscosity. It cannot, however, completely reverse the disappearance of cartilage, nor can it reverse bone loss caused by arthritis.
caption: The cartilage matrix. The joint space is filled with synovial fluid. Glycosaminoglycans are attached to proteins, which are attached to a strand of hyaluronic acid to create a "bottle brush".
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