Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors

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.

Figure 1

Activation of mitogen-activated protein kinase (MAPK; shown in yellow) pathways by IL-1. Stimulation by IL-1 activates the MAPK kinase kinases (MAPKKKs; shown in blue), transforming-growth-factor-β-activated kinase-1 (TAK 1) and Raf, which then phosphorylate and activate several MAPK kinases (MAPKKs; shown in green): MKK6, MKK4, MKK7, MEK. These MAPKKs in turn phosphorylate and activate the MAPKs, p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), which translocate to the nucleus. There, these MAPKs phosphorylate and activate the transcription factors (activating transcription factor 2 [ATF2], c-Jun, Elk-1 and erythroblastosis twenty-six [Ets]-1; shown in red) that contribute to matrix metalloproteinase (MMP) transcription. IL-1R, IL-1 receptor; IL-1RAcP, IL-1 receptor-associated protein; IRAK, IL-1 receptor activated kinase; SRF, serum response factor; TAB, Tak-binding protein; TRAF, TNF receptor-associated factor.

Figure 2

Activation of the NF-κB pathway by IL-1. IL-1 binds to its receptor (IL-1R1) and receptor-associated protein (IL-1RAcP), causing conformational changes in multiple receptor-bound proteins (MyD88, IRAK, TRAF6, TAB2; see Figure 1 for definition). This results in recruitment and activation of transforming-growth-factor-κ-activated kinase-1 (TAK 1), which phosphorylates and activates NF-κB-inducing kinase (NIK). In turn, NIK activates the inhibitor of κB kinase (IKK) complex, which is responsible for phosphorylation of inhibitor of κB (IκB) and NF-κB1 (a 105 kDa protein, p105). Upon phosphorylation, IκB and p105 become polyubiquitinated (U), which targets these proteins for degradation by the proteosome. Degradation of these cellular inhibitors allows translocation of NF-κB subunits to translocate to the nucleus and transactivate matrix metalloproteinase (MMP) promoters. The IκB-like protein, Bcl-3, promotes dimerization of the 50 kDa NF-κB subunit (p50) and regulates the transcriptional activity of p50.