Review of Physiology Modifiers: Hyaluronan, Polysulfated Glycosaminoglycan, and Tiludronate

Hyaluronans have been used and studied in horses and humans since the 1970s. Most hyaluronan preparations are a 1% concentration with a molecular size of anywhere between 500,000 and 6,000,000 Daltons. Hyaluronan has been shown to interact with the CD44 receptor to modulate cell proliferation, migration, and gene expression. It has also been shown to decrease proinflammatory mediators and pain-producing neuropeptides that are common in the joint and lead to disease. In vitro, hyaluronan has shown a positive effect on chondrocyte morphology in articular cartilage explants, it stimulated proteoglycan synthesis in both chondrocyte and articular cartilage explant cultures, and it has also been shown to decrease prostaglandin E2 (PGE2) by synoviocytes in a lipopolysaccharidestimulated model. Hyaluronan has also been shown to reduce shear strain after injury, probably leading to a decrease in post-injury trauma, and to have a positive effect when combined with corticosteroids such as with triamcinolone or methylprednisolone acetate. However, in vitro studies have shown mixed results in the face of corticosteroids, as one study showed little effect of hyaluronan on methylprednisolone acetate–induced articular cartilage matrix catabolism, and another showed that exogenous hyaluronan in combination with corticosteroids decreased the proteoglycan release typical of corticosteroid administration alone. There has also been some indication that molecular weight may have an influence on the efficacy of hyaluronan. One in vitro study showed that lowand medium-molecular-weight hyaluronan actually increased inflammation, whereas high-molecularweight hyaluronan decreased inflammation. This was shown to occur via binding to the CD44 receptor and led to the conclusion that CD44 receptor may modulate inflammation via hyaluronan mass. Santangelo et al. showed that hyaluronan was protective of lipopolysaccharide-induced fibroblast changes in vitro and that high-molecular-weight hyaluronan had a greater effect than low-molecularweight compounds. Although in vitro studies have shown an effect of molecular weight, variable effects