Abstract

The major pathologic manifestations of rheumatoid arthritis (RA) and osteoarthritis (OA) are joint inflammation and articular cartilage resorption by proinflammatory cytokine-stimulated matrix metalloproteinases (MMPs) and aggrecanases. The Chinese herbal remedyTripterygium wilfordii Hook F (TWHF) is effective for treatment of various types of arthritis. However, mechanisms and targets of its actions are poorly understood. Anti-inflammatory activities of the extracts of this plant were previously attributed to inhibition of cyclooxygenase-2 mRNA and prostaglandin E₂synthesis. Here, we show that in primary human femoral head osteoarthritic and normal bovine chondrocytes, TWHF partially or completely inhibited mRNA and protein expression of tumor necrosis factor-α, interleukin (IL)-1, and IL-17-inducible MMP-3 and MMP-13. This agent also inhibited cytokine-stimulated MMP-3 protein expression in human synovial fibroblasts. A dose range of 2.5 to 10 ng/ml of TWHF was effectively inhibitory for IL-1. Pretreatment for 30 min or 1 h (but not 2–10 h) after IL-1 treatment with TWHF inhibited MMP-3 RNA induction. The inhibitory doses had no adverse effect on the viability of chondrocytes. Mechanistic studies revealed no impact on the activation of extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase mitogen-activated protein kinases. Instead, TWHF partially inhibited DNA binding capacity of cytokine-stimulated activating protein-1 (AP-1) and nuclear factor-κB (NF-κB) transcription factors. Therefore, besides its anti-inflammatory activity, this agent may also be effective in blocking cartilage matrix resorption by MMPs by impairing AP-1 and NF-κB binding activities. Thus, TWHF extract contains novel inhibitors of MMP expression that may be of therapeutic potential in arthritis and other conditions associated with increased MMPs.