Matrix metalloproteinases (MMPs) degrade extracellular matrix components, and overexpression of these enzymes contributes to tissue destruction in arthritis. Of particular importance are the collagenases, MMP-1 and MMP-13, which have high activity against the interstitial collagens in cartilage. In this study, we address the mechanisms of two inhibitors of collagenase gene expression, the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and 15-deoxy-Δ(12,14)-prostaglandin J₂ (15-dPGJ₂). Although both inhibitors are ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor-γ (PPAR-γ), a connection between PPAR-γ and collagenase gene expression has yet to be established. Here, we test the hypothesis that CDDO and 15-dPGJ₂ use PPAR-γ to repress MMP gene expression. Our findings with the PPAR-γ antagonist 2-[4-[2-[3-(2,4-difluorophenyl)-1-heptylureido]ethyl]rsqb]-phenylsulfanyl]-2-methylpropionic acid (GW9662) and mouse embryonic fibroblasts lacking PPAR-γ demonstrate that CDDO and 15-dPGJ₂ use PPAR-γ-independent mechanisms to inhibit collagenase gene expression. To address a potential PPAR-γ-independent mechanism leading to the repression of MMPs by CDDO, we tested the effect of CDDO on the transforming growth factor-β (TGF-β) signaling pathway. We found that CDDO requires Smads (transcription factors activated by TGF-β) for the repression of MMP-1. Specifically, MMP-1 is inhibited neither by CDDO in the absence of TGF-β receptor-activated Smad3 nor when a negative regulator, Smad7, attenuates TGF-β signaling. We conclude that CDDO represses MMP gene expression through a novel PPAR-γ-independent mechanism that requires Smad signaling.