Tripterygium wilfordii Hook F extract suppresses proinflammatory cytokine-induced expression of matrix metalloproteinase genes in articular chondrocytes by inhibiting activating protein-1 and nuclear factor-kappaB activities.
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 remedy Tripterygium 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 E(2) synthesis. 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-alpha, 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-kappaB (NF-kappaB) 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-kappaB 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.
Sylvester
J
J
Département de Médecine and Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CHUM), Hôpital Notre-Dame du CHUM, Québec, Canada.
Liacini
A
A
Li
W Q
WQ
Dehnade
F
F
Zafarullah
M
M
D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000201:enzymology; D017364:Collagenases / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D004365:Drugs, Chinese Herbal / Q000737:chemistry*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010936:Plant Extracts / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D029757:Tripterygium
D016207:Cytokines; D004365:Drugs, Chinese Herbal; D016328:NF-kappa B; D010936:Plant Extracts; D018808:Transcription Factor AP-1; D004247:DNA; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3