Degradation by Nonenzymatic Means

In contrast to being a chemical compound stable under normal physiological conditions, chain scission of the HA polymer can be induced in an unspecific manner by chemical reactions other than enzyme-catalyzed degradation as well as by physical stresses such as freeze-drying, shearing or stirring at critical conditions. Moreover, irradiation can cause depolymerization. In line with this, it was found that free radicals can interact with HA and cause degradation of the polymer (53).

Cells form reactive oxygen species (ROS) as a consequence of normal aerobic respiration. Several candidates have been described to cause HA chain scission such as the superoxide anion, the hydroxyl radical (54) or hypochloride and species derived from peroxynitrite (55). ROS are suggested to be involved in several biodegenerative and inflammatory processes such as arthritis, but evidence for them participating in disease, still remains circumstantial. However, depolymerization of HA in synovial fluids during the early onset of inflammatory arthritis is believed to be caused by ROS and not by hyaluronidases (56).

Normal synovial fluid is viscoelastic, which is largely determined by the presence of high molecular weight HA. The normal high levels (2-4 g/L) of HA (average molecular weight 7 X 106 Da) in healthy joints are essential for functional joint articulation. Synoviocytes continuously secrete macromolecules into the synovial fluid including HA. Fluid is pushed out of the joint cavity into microcapillaries embedded in the synovium every time the pressure is raised. In this way, HA molecules escape through the interstitial drainage pores in the synovial lining (diameter 30-90 nm), but with decreased motility compared to smaller molecules (Fig. 2). It is believed that high molecular weight HA forms a layer at the tissue-fluid interface, not to be absorbed by the microcapillaries (57). The normal intra-articular turnover time for HA is <40 h. However, in arthritis

Figure 2 Drainage of HA from the synovial fluid to the lymphatic system. HA is primarily synthesized by fibroblast-like cells. High molecular weight HA can be taken up into the lymphatics at a low rate (slim arrow). Fragmented chains can pass the interstitial drainage pores embedded in the matrix at an elevated rate indicated by the bold arrow. Concentration (c) and molecular weight (Mr) of HA are indicated.

Figure 2 Drainage of HA from the synovial fluid to the lymphatic system. HA is primarily synthesized by fibroblast-like cells. High molecular weight HA can be taken up into the lymphatics at a low rate (slim arrow). Fragmented chains can pass the interstitial drainage pores embedded in the matrix at an elevated rate indicated by the bold arrow. Concentration (c) and molecular weight (Mr) of HA are indicated.

patients both HA chain length and HA concentration are decreased, consequently leading to significantly reduced lubricant viscosity. It is widely believed that this is being evoked by ROS, because treatment with radical scavengers inhibits degradation of HA.

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