Effect of heparinoid on the production of tissue inhibitor of metalloproteinases (TIMP)-3 in rheumatoid synovial fibroblasts

Abstract

Heparinoid is one of the major contents of Mobilat widely used as an antirheumatic drug. To clarify the precise mechanisms of the antirheumatic effect of heparinoid, we investigated its effects on the production of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) from rheumatoid synovial fibroblasts stimulated (or not) with interleukin-1 alpha (IL-1α) at 100 units mL−1. The expression of TIMP-3 mRNA was also investigated in a similar manner. The production of both MMPs and TIMPs and the expression of TIMP-3 mRNA were investigated by western-blot analysis and northern-blot hybridization, respectively. Under the stimulation of IL-1α, heparinoid increased the production of TIMP-3 in a concentration-dependent manner, but not TIMP-1, TIMP-2, MMP-1 or MMP-3. Heparinoid did not affect the expression of TIMP-3 mRNA that was increased by the stimulation of IL-1α. These findings suggest that the anti-rheumatoid effect of heparinoid may be due to increased production of TIMP-3. This increase in TIMP-3 may help redress the imbalance between the amounts of MMPs and TIMPs as observed in the joint tissues of rheumatoid arthritis and osteoarthritis patients.