Abstract
Matrix metalloproteinase (MMP)-1, MMP-8 and MMP-13 are interstitial collagenases that degrade type II collagen in cartilage; this is a committed step in the progression of rheumatoid arthritis and osteoarthritis. Of these enzymes, the expression of MMP-1 and MMP-13 is substantially increased in response to IL-1 and tumor necrosis factor-alpha, and elevated levels of these collagenases are observed in arthritic tissues. Therefore, cytokine-mediated MMP-1 and MMP-13 gene regulation is an important issue in arthritis research. In this review, we discuss current models of MMP-1 and MMP-13 transcriptional regulation, with a focus on signaling intermediates and transcription factors that may be future targets for the development of new arthritis drugs.
Highlights
The matrix metalloproteinase (MMP) family members are the major enzymes that degrade the components of the extracellular matrix [1,2]
In addition to c-jun, the extracellular signal-regulated kinases (ERKs) pathway regulates the activity of erythroblastosis twenty-six (Ets) transcription factors [24,25], which cooperate with activating protein-1 (AP-1) proteins in multiple MMP promoters
In the remainder of this review, we address how these pathway-specific signals lead to the recruitment of a cohort of transcription factors that cooperate to initiate MMP-1 and MMP-13 transcription
Summary
The matrix metalloproteinase (MMP) family members are the major enzymes that degrade the components of the extracellular matrix [1,2]. In addition to c-jun, the ERK pathway regulates the activity of erythroblastosis twenty-six (Ets) transcription factors [24,25], which cooperate with AP-1 proteins in multiple MMP promoters. By promoting expression of AP-1 genes, p38 may indirectly contribute to MMP transcription Another major cytokine-induced signaling pathway involves translocation of nuclear factor-κB (NF-κB) family members from the cytoplasm to the nucleus (Fig. 2). 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 [53]. Direct blockade of the NF-κB pathway, at least in joint cells, may be a viable therapy to reduce MMP transcription in arthritis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
