Resveratrol Inhibit Interleukin - 1 - Induced Adamts - 4 ( Aggrecanase - 1 ) Gene Expression in Articular Chondrocytes : Natural Products as Potential Anti - Arthritic Agents

Interleukin-1 (IL-1β) is the main proinflammatory cytokine stimulant of cartilagedegeneration in arthritis. Aggrecanases (ADAMTS or A Disintegrin And Metalloproteinase with ThromboSpondin motifs) are enzymes implicated in tissue remodeling and cleavage of aggrecan core protein between Glu-Ala, a major structural protein of cartilage extracellular matrix giving its characteristic compressive stiffness. This study screened for natural products with the ability to inhibit IL-1-induced ADAMTS-4 gene expression in human articular chondrocytes. Confluent normal human knee articular chondrocytes were pretreated either with natural products at different doses and stimulated further for 24 h with IL1β (10 ng/ml). ADAMTS-4 and glyceraldehydes-3-phosphate dehydrogenase (GAPDH) RNA levels were analyzed by RT-PCR. IL-1β induced ADAMTS-4 RNA in high-density human chondrocyte monolayer cultures. Pretreatment with a leukotreine and c-Fos (component of activating protein or AP-1 transcription factor) inhibitor, nordihydroguiaretic acid (NDGA) suppressed the ADAMTS-4 RNA induction. Quercetin and Resveratrol at 50-100 μM partially reduced ADAMTS-4 RNA induction. Further AP-1 and nuclear factor kappa B (NF-κB) transcription factors inhibitor, curcumin partially inhibited aggrecanase-1 induction. The levels of internal control, GAPDH RNA remained consistent. Thus several natural products can interfere with proinflammatory cytokine signal transduction pathways or their target transcription factors and thus inhibit IL-1-induced ADAMTS-4 in chondrocytes. Such inhibition warrants further studies on toxicology and potential for reducing ADAMTS-4-driven cartilage resorption in arthritis.