Viscosupplementation: Evidence for a Mechanism of Action
Authors: DD Waddell et al.
References: Presented at AAOS 2004
Hyaluronan in this study reduced MMP activity induced by IL-1 of synovial cells in osteoarthritis patients.
INTRODUCTION: Viscosupplementation is approved for treating pain due to osteoarthritis (OA). One possible mechanism is the reduction in expression of cartilage-destroying enzymes (metalloproteinases (MMPs)), which are produced in response to proinflammatory cytokines such as IL-1. We hypothesized that hyaluronan (HA), the substance used in viscosupplementation, reduced MMP activity of synovial cells in OA patients induced by IL-1.
METHODS: Surgical biopsies (0.12 square cm, +/-15 percent) were obtained from 20 patients undergoing total-knee replacement for OA. The biopsies were cultured for 24 hrs in serumless medium in the presence or absence of IL-1 (100 pg/ml) and HA (8 mg/ml), and the MMP activity of the supernatant (principally collagenase) was measured using a film of collagen as the substrate. The three HA products approved by FDA for viscosupplementation and one additional HA were studied. The HA’s and their respective molecular weights were: Synvisc (6 MDa); Supartz (0.6-1.1 MDa); Hyalgan (0.5 MDa); 0.2 MDa HA (Lifecore). The effect of HA on the IL-1-induced MMP production was evaluated using the unpaired t-test; enzyme activities are expressed in units of mg of substrate digested per hour per square meter.
RESULTS: The synovial biopsies produced a constitutive MMP activity of 2.7+/-1.2, which was increased 16-fold (to 44.7+/-4.8) in response to treatment with IL-1. When 0.2 MDa HA was added together with the cytokine, the MMP activity was unaffected (45.0+/-5.5). The MMP activities measured in the presence of IL-1 and viscosupplementation HA’s were: 27.9+/-5.7, Hyalgan; 7.8+/-4.3, Supartz; 3.6+/-1.1, Synvisc (P<0.05 compared with IL-1 alone for all 3 HA’s). Fat biopsies produced only a negligible amount of MMP activity, indicating that the enzymatic activity in the synovial biopsies was produced by synovial cells.
CONCLUSION: Viscosupplementation HA’s blocked the IL-1-induced MMP activity produced by synovial cells in a process that depended on HA molecular weight; maximum inhibition occurred at the highest molecular weight (6.1 MDa). It is not possible to reach conclusions regarding the relative abilities of the HA’s to inhibit cytokine-induced MMP activity when the HA’s are used at the FDA-approved concentrations (10 mg/ml, except 8 mg/ml for Synvisc). Even so, the results established that the viscosupplementation HA’s can inhibit cytokine-induced MMP activity, as hypothesized, suggesting that the mode of action of HA might be due to reduced MMP activity with concomitant reduction in inflammatory-mediated pain.