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Objective: We have previously shown that interleukin-1[beta] (IL-1[beta]) impairs transforming growth factor [beta] (TGF[beta]) signaling through TGF[beta] receptor type II (TGF[beta]RII) down-regulation and Smad7 up-regulation. This mechanism could account for the reduced responsiveness of osteoarthritic chondrocytes to TGF[beta] and the cartilage breakdown linked to this disease. The aim of this study was to investigate the molecular mechanism underlying the IL-1[beta]-induced stimulation of Smad7 in human articular chondrocytes.

Methods: Human articular chondrocytes were treated with IL-1[beta] in the presence of TGF[beta]1, pyrrolidine dithiocarbamate (a repressor of the NF-[kappa]B pathway), or cycloheximide. Then, steady-state messenger RNA and protein levels were estimated by real-time reverse transcription-polymerase chain reaction and immunocytology. In addition, transient transfections of p65 expression vector or p65-targeted short hairpin RNA were performed to define the effect of NF-[kappa]B on Smad7 expression.

Results: TGF[beta]RII overexpression restored the TGF[beta] response of human articular chondrocytes. However, this effect was transient, implying that a secondary mechanism was responsible for the alteration of the TGF[beta] response with long-term exposure to IL-1[beta]. Moreover, IL-1[beta] caused a late induction of the inhibitory Smad7. This effect was direct, since it did not require de novo synthesis. In addition, we established, by experiments with gain/loss of function, that the up-regulation of Smad7 by IL-1[beta] is mediated through the NF-[kappa]B pathway, especially the p65 subunit.

Conclusion: These findings clarify the regulatory process of IL-1[beta] on Smad7 expression. Understanding the molecular basis of IL-1[beta] induction of Smad7 and the reduction of chondrocyte responsiveness to TGF[beta] provides new insights into the molecular mechanisms of osteoarthritis and may facilitate the identification of novel approaches for its treatment.

(C) 2008, American College of Rheumatology