Intra-articular hyaluronan: A disease modifying therapy?

Abstract

Hyaluronan (HA) is a macromolecular glycosaminoglycan which is an important constituent of both synovial fluid and the extracellular matrix of cartilage. Research into the functions of HA have suggested a number of different biophysical, biochemical and cell regulatory roles in joint synovial tissues. Intra-articular HA therapy is now widely used in various countries for the treatment of osteoarthritis (OA) in both humans and animals. Numerous high purity pharmaceutical preparations are commercially available which have a variety of forms and molecular weights ranging from less than 1.0 × 106 Da (generally regarded as low molecular weight) up to 3–6.0 × 106 Da (high molecular weight). This range of molecular weights in the commercially available preparations is a direct reflection of the variation in results derived from both in vitro and in vivo studies of the use of HA in various experimental models. Intra-articular HA therapy has been registered by some companies as a device rather than a drug, which reflects both the initial theory that HA exerted its action through viscosupplementation of deficient synovial fluid, and the current scientific debate as to the specific therapeutic effects of HA on synovial tissues. Significant research is ongoing to further define the likely multiple actions of HA on joint tissues. The discovery that HA is rapidly cleared from joints after intra-articular injection, coupled with the realization that the symptomatic relief experienced by human OA patients treated by intra-articular HA, together suggest that viscosupplementation is not the only mode of action of HA. Studies in various animal models of inflammation and pain have supported an anti-inflammatory action of HA in joint disease. In vivo animal studies using models of OA suggest that low molecular weight HA provides better protection of cartilage than high molecular weight preparations. This is in direct contrast to the results of in vitro studies using chondrocyte or cartilage explant cultures in which high molecular weight HA preparations were found to be more effective at protecting cartilage from degradation than low molecular weight preparations. Evidence that low molecular weight forms of HA penetrate the joint tissues more deeply is a partial explanation for this, as it is likely that the low molecular weight HA is able to achieve higher concentrations of the drug in the pericellular environment. However, recent research has provided additional evidence of specific interaction between HA, various cell receptors such as CD44. This, together with other studies in cell biology which have demonstrated that signal transduction and gene expression arise from HA receptor binding suggest an immunoregulatory role for HA. Our present knowledge of interactions of HA at the cellular and molecular level is still inadequate, but there is strong evidence from animal model experiments as well as from studies on human synovial biopsies that the positive effects exhibited by HA in OA joints are largely mediated by its anti-inflammatory, cytoprotective and immunoregulatory properties. There is significant scientific evidence that intra-articular HA therapy can provide cartilage protection. However, this probably does not arise from a direct effect of HA on chondrocytes, but rather is secondary to the down regulation of cytokine, free radical and proteolytic activities in the synovial fluid and synovium, all of which can adversely affect chondrocyte metabolism.