The potential of signal transduction inhibitors for the treatment of arthritis: Is it all just JNK?

Abstract

Rheumatoid arthritis (RA) is a connective tissue disease that affects more than 1,000,000 people in the US (1). This autoimmune disorder is driven largely by the recruitment of activated immune cells (T and B cells) and macrophages to the afflicted joints. There, the cytokines IL-1 and TNF, which are produced by these cells, mediate the irreversible joint destruction seen in RA (2). The downstream genes activated by these cytokines encode both inflammatory molecules and secreted proteinases of the matrix metalloproteinase (MMP) family (3). The interstitial collagenases (collagenase-1, MMP-1; collagenase-2, MMP-8; collagenase-3, MMP-13; MT1-MMP, MMP-14) act at a committed step in the progression of RA, degrading type II collagen in cartilage (1, 3). Of these enzymes, particular attention has focused on MMP-1 and MMP-13 because they are induced in response to IL-1 and TNF and are found at elevated levels in RA (4). Therefore, inhibition of cytokine-induced MMP-1 and MMP-13 gene expression has been a prime target for the development of new arthritis drugs. Earlier studies identified sequences in the promoters of these two MMP genes that mediate the increase in gene expression, including a proximal AP-1 site that binds members of the Fos and Jun families of transcription factors (5, 6), and several upstream sequences such as an NF-κB–like element (7) and a Cbfa1/OSF2/RUNX-2 (RUNX-2) binding site (8). Mutational and deletional analysis has indicated that these upstream sites cooperate with the proximal AP-1 site in order to drive transcription (7, 9, 10). Further, although both MMP-1 and MMP-13 expression increases with cytokine stimulation, this increase is somewhat cell type–restricted and differs somewhat between the two genes. The restricted expression of MMP-13 in osteoblasts and chondrocytes may reflect the predominant expression in these cells of RUNX-2, which activates the MMP13 but not the MMP1 promoter (8, 11) (J.A. Mengshol and C.E. Brinckerhoff, unpublished work). In contrast, cytokines induce MMP-1 expression in virtually all human connective tissue cells (4), clearly indicating that the mechanisms controlling expression of these two collagenases differ. Recent studies have begun to analyze signal transduction pathways for their possible role in the transcriptional activation of MMP-1 and MMP-13 in cells associated with arthritic disease. The enzymes that facilitate these pathways are termed the mitogen-activated protein kinases (MAPKs) (12) and include the c-Jun N-terminal kinases (JNKs), the extracellular signal–regulated kinases (ERKs), and the p38 kinases. The availability of chemical compounds that can specifically block one or another signal transduction pathway has greatly aided these studies (Figure ​(Figure1).1). In a recent issue of the JCI, Han et al. (13) in the laboratory of Gary Firestein describe the ability of a new inhibitor, SP600125, to specifically block JNK, thus providing a tool to investigate the role of this kinase in MMP gene expression and in the pathophysiology of RA. They show that SP600125 completely blocks IL-1–induced expression of c-Jun and collagenase mRNAs and prevents the accumulation of phospho-Jun in cultured synovial cells. The in vitro binding of nuclear proteins to an AP-1–containing DNA fragment is likewise severely inhibited, consistent with evidence that this cis-acting sequence is a major target of IL-1 induction, apparently as a result of JNK activation. Figure 1 IL-1 activation of MAPK pathways. IL-1 binds to its cellular receptor and activates receptor-associated proteins (red), such as IRAK, TRAF6, and TAK1. The result is activation of several MAPK kinases (MKK6, MKK4, MKK7, and MEK1; green), which phosphorylate ... These results may suggest a central role for the pathway, at least in cultured cells, but the data are slightly less clear-cut in the animal studies, since the authors observe incomplete silencing of collagenase mRNA induction and only a partial inhibition of joint destruction in SP600125-treated rats. Other pathways may contribute to this pathological process. Alternatively, other cells, in addition to synovial fibroblasts, or other proteinases, in addition to the well studied MMPs, may be involved joint destruction.