Hyaluronan enhances cartilage repair through low grade tissue remodeling involving cytokines and matrix metalloproteinases

Objective and design: To determine whether the ability of high molecular weight hyaluronan (HA) to reverse cartilage damage caused by specific catabolic mediators of cartilage damage, fibronectin fragments (Fn-fs), occurs through a low grade of enhanced catabolic events such as enhanced matrix metalloproteinase (MMP) expression or cytokine activities. Material: HA from 6.8-kDa to 2 million daltons was studied. Treatment: The ability of HA to enhance matrix metalloprotemase-3 (MMP-3) epitopes and cartilage proteoglycan (PG) degradation neoepitopes was tested in bovine cartilage, as well as the ability of recombinant human interleukin-1 receptor antagonist protein (rhIRAP) to reverse PG depletion in cartilage first exposed to Fn-f. Results: All HA forms enhanced MMP-3 epitopes and PG degradation in normal undamaged cartilage and in the case of HA800, the degradation was not sufficient to decrease steady state levels of cartilage PG. When HA800 was added to Fn-f damaged cartilage, restoration of PG occurred, but this was blocked by rhIRAP. Conclusions: These results collectively suggest that some of the repair activity of HA800 is through proteolytic activity which is not sufficient to decrease matrix PG content, but is nonetheless elevated above levels in cartilage not treated with HA800. ECL, enhanced chemiluminescent; HRP, horse radish peroxidase; IGF-1, insulin-like growth factor; recombinant human IGFBP, insulin like growth factor binding protein; rhIRAP, recombinant human interleukin receptor antagonist protein; DMEM, Dulbecco's modified Eagle's medium; S.D., standard deviation; DMB, dimethylmethylene blue.