Using glycosaminoglycans for treating equine joint diseases

Using glycosaminoglycans for treating equine joint diseases

Nov 01, 2003

During the past 20 years medical therapy for non-septic equine joint diseases and injuries has been greatly enhanced by the use of drugs classified as glycosaminoglycans (GAGs). These compounds have allowed us to direct our therapies toward the underlying pathology of equine joint disease and in many cases extend the useful careers of athletic horses. There has been an explosion in the numbers and types of these products available. Many are supported by solid scientific research and are manufactured and marketed under approval by the U.S. Food and Drug Administration (FDA). FDA approval assures that a product is safe and effective as demonstrated in controlled studies and is manufactured under strict guidelines to assure purity and potency. Others have weak or no scientific support and their manufacturing is subjected to little or no regulation. It is important that veterinarians and horse owners understand all GAG products are not equal.

What are GAGs? Glycosaminoglycans are polysaccharides made up of repeating disaccharide units and are an important component of many connective tissues including tissues in the equine joint. The most important GAGs in the equine joint are hyaluronic acid, chondroitin sulfate and keratin sulfate.

Figure 1: Comparative molecular structure of glucosamine, hyaluronic acid, Chondroitin Sulfate and PSGAG
Hyaluronic acid (HA) is a non-sulfated GAG (Figure 1) that is produced by cells in the synovial membrane and released into the synovial fluid. Here these long chain molecules function as the barrier lubricant of the synovial membrane and joint capsule and help to form the synovial barrier. This barrier helps keep cells and large molecules out of the synovial fluid. The health of a joint is dependent on normal synovial fluid HA content. HA is also said to be a component of articular cartilage lubrication at low loads. HA is also a critical component of proteoglycan complexes (Figure 2, p. 9). A molecule of HA forms the "backbone" of the large proteoglycan complexes.

Chondroitin and keratin sulfates are sulfated GAGs and are also important components of the proteoglycan complexes in articular cartilage matrix. Side chains of these GAGs are attached to a protein core to form a large molecular aggregate (Figure 2). The negative charges from carboxyl and sulfate radicals cause these side chains to repel each other. Water is drawn into the spaces between the GAG side chains. This arrangement contributes to the ability of cartilage to distribute forces acting upon it and allows cartilage to change shape and comply with loads then resume its resting shape when loads are removed.

In joint inflammation and injury, these GAG components can undergo degredation due to direct injury and to the action of inflammatory mediators and catabolic enzymes. Reduced concentration and a decrease in the mean molecular weight of synovial fluid HA are early effects of synovial inflammation. The proteoglycan complexes may also be damaged or degraded and diseased cartilage is often characterized by depletion of GAG content.

The restoration of normal synovial fluid hyaluronate and repair or replacement of GAGs and other cartilage matrix components should be one of the goals of therapy for equine joint injuries.

Figure 2: Proteoglycan Complex
Pharmaceutical GAGs approved for equine joint disease There are two types of GAGs approved for the therapy of joint disease and injury in the horse. The first is sodium hyaluronate, the sodium salt of HA. There are four FDA products approved for intraarticular use in horses: Legend" Injectable Solution (Bayer), Hylartin-V" (Pfizer), Hyvisc" (Boehringer Ingleheim), and Hyalovet" (Fort Dodge). One product is approved for intravenous use, Legend" Injectable Solution. The efficacy of sodium hyaluronate has been well established. The drug is anti-inflammatory by several mechanisms and may stimulate endogenous HA production. Treatment helps to normalize the synovial environment. HA probably does not have direct effects on diseased cartilage but may help protect cartilage through its anti-inflammatory effects on synovial tissue. Efficacy and safety have been confirmed by the required dose, efficacy and safety studies for FDA approval as well as independent research and more than 20 years of clinical experience. There have been more than 15 published reports of clinical or experimental studies that support the efficacy of intraarticular sodium hyaluronate in the horse. Intravenous sodium hyaluronate is also supported by dose, efficacy and safety studies required for FDA approval as well as independent studies in two equine joint disease model test systems. The HA products are indicated for the treatment of joint dysfunction due to non-infectious synovitis associated with equine osteoarthritis.

The second approved GAG is polysulfated glycosaminoglycan or Adequan" (Luitpold). PSGAG is synthetically polysulfated chondroitin sulfate (Figure 1) which means it has a higher sulfur content compared to chondrotin sulfate. The drug is approved for intrarticular and intramuscular use in equine joint disease. The drug is anti-inflammatory, inhibits enzymes which may degrade GAGs and HA in the joint and may have a positive effect on HA and GAG synthesis in diseased joints. For this reason, PSGAG is said to be a disease modifying osteoarthritis drug. Optimal dose, efficacy and safety studies for FDA approval by the intraarticular and intramuscular route was established in six well controlled studies. Efficacy has been confirmed by at least 10 published experimental or clinical studies in the horse and nearly 20 years of clinical experience. Adequan" is indicated for the treatment of non-infectious degenerative and/or traumatic joint dysfunctions and associated lameness in the horse.