Since joint destruction in arthritic diseases is not reversible, the inhibition of the proteases responsible for cartilage degradation is an important part of therapy. While potent inhibitors of MMP enzymatic activity have been developed, their use has been limited due to safety issues . Inhibition of MMP gene expression at the transcriptional level may be a viable alternative option. With the exception of the glucocorticoid hormones, however, none of the several compounds now available to reduce MMP transcription are in clinical use, although some have been used successfully in animal models of arthritis.
The glucocorticoids bind to their receptors (GRs), which then usually interact with glucocorticoid response elements present in the promoters of many genes . Because the MMP promoters do not contain glucocorticoid response elements, inhibition of transcription occurs through an indirect mechanism. This 'transrepression' involves binding of the activated receptor to Fos and Jun proteins present at the proximal AP-1 site, with a subsequent change in their conformation and a reduction in transcription . Activated GRs can also potently repress NF-κB-dependent transcription by two separate mechanisms. First, GRs physically interact with RelA/p65, resulting in inhibition of NF-κB-dependent transcription [54,55]. This interaction is specific for p65, and is distinct from the domain involved in AP-1 transrepression . Second, glucocorticoids enhance IκBα synthesis, resulting in sequestration of NF-κB in the cytoplasm.
The vitamin A analogues, retinoids, also block MMP transcription through the AP-1 site [57–60]. Ligand activated receptors (e.g. the retinoic acid receptors α, β and γ, and the retinoid × receptors α, β and γ) reduce MMP transcription by binding to Fos and Jun proteins at the AP-1 site, sequestering these proteins away from the promoter and/or reducing the level of Fos and Jun mRNAs . Although retinoids have reduced joint destruction in animal models of arthritis , they have not been used in patients. In addition, both glucocorticoids and retinoids affect a broad number of genes, and this lack of specificity may contribute to the side effects associated with these compounds.
There is one novel compound that may block the expression of specific MMPs in arthritis. This is a synthetic triter-penoid, 2-cyano-3,12-dioxoolean-1,9,dien-28-oic acid (CDDO) [63,64]. At nanomolar concentrations, CDDO selectively inhibits the induction of MMP-1 and MMP-13 by inflammatory cytokines in IL-1-stimulated chondrosar-coma cells, without affecting basal expression . In addition, the expression of other MMPs is not affected, and thus the low constitutive levels of MMPs required for normal physiology may remain untouched. CDDO inhibits MMP-1 and MMP-13 gene expression, at least in part, by reducing IL-1-induced transcription . While this mechanism is not fully understood, this drug is known to be a ligand for peroxisome proliferator-activated receptor-γ (PPAR-γ) ; other PPAR-γ agonists such as 15-deoxyprostaglandin J2 can also inhibit MMP-13 synthesis . Since PPAR-γ can physically interact with c-Jun, it is tempting to speculate that CDDO treatment induces an AP-1/PPAR-γ association that is transcriptionally repressive. Additional work is required to determine if CDDO represses in an AP-1-dependent manner, or if it works through a novel mechanism to repress MMPs.
Finally, increased knowledge of the specific signal/transduction pathways driving MMP-1 and MMP-13 expression in arthritic chondrocytes and synovial cells has led to the search for agents that can inhibit these pathways. Blocking MAPK pathways inhibits gene expression of MMPs in tissue culture experiments, and prevents progression of arthritis in animal models. For example, the p38 MAPK inhibitor, SB203580, blocked MMP-13 gene expression in cultured chondrocytes  and inhibited IL-1 mediated collagen degradation in cartilage explants . In the collagen-induced arthritis model of rheumatoid arthritis, SB203580 significantly inhibited TNF-α and IL-6 production, reduced paw inflammation, and inhibited the formation of joint lesions . In addition, orally active p38 inhibitors were also effective in animal models of inflammatory arthritis [69,70] presumably by blocking MMP synthesis. Inhibition of JNK by the novel inhibitor SP600125 inhibited bone destruction in adjuvant-induced arthritis, suggesting a role for this MAPK in disease pathogenesis .
Since NF-κB activation is required for the expression of MMP-1 and MMP-13, as well as inflammatory stimuli such as IL-1, IL-6 and TNF-α [7,29,71,72], this pathway is another potential therapeutic target. This is supported by the work of Bondeson et al. , in which over-expression of IκBα reduced expression of inflammatory cytokines and MMPs, but did not reduce anti-inflammatory cytokines or tissue inhibitor of metalloproteinases. Furthermore, mice deficient in the p50 subunit are refractory to collagen-induced arthritis , indicating that this factor has a prominent role in arthritic disease. Indeed, p50 was the only subunit found to bind to an IL-1-responsive element of the MMP-1 promoter . Thus, direct blockade of the NF-κB pathway, at least in joint cells, may be a viable therapy to reduce MMP transcription in arthritis.