Regulation of chondrocyte matrix metalloproteinase gene expression

Abstract

Matrix metalloproteinases also known as MMPs are zinc-dependent endoproteases which process extracellular matrix proteins at neutral pH to regulate normal macromolecular protein turnover as well as those cellular events associated with the remodeling of tissue architecture. The MMP superfamily of proteins include the classical MMPs, MMP-1, -8, -13, and -18, the gelatinases, MMP-2, -9, stromelysins, MMP-3, -10, -11, matrilysins, MMP-7, MMP-26, membrane-type MMPs (MT-MMPs; MMP-14, -17, 24/25) the ADAMS (a d isintegrin a nd m etalloproteinase) also known as adamlysins and the ADAMTS (a d isintegrin a nd m etalloproteinase with t hrombo s pondin motif). MMP genes are regulated principally via the activation of transcription factors induced by various growth factors and cytokine/ cytokine receptor interactions which are pertinent to the tissue allostasis, but which are most critical to the pathophysiological progression of rheumatoid arthritis and osteoarthritis. The most important transcription factors known to be involved in regulating MMP gene expression include the synthesis and/or activation of NF-κB, Cbfa1, AP-1, Nmp4/CIZ, ELF3, c-Maf, KLF5 and Sp1 which interact with specifi c known sequences in the promoter region of MMP genes. In arthritis, protein kinase pathways are generally activated by pro-infl ammatory cytokines, including interleukin-1ß, tumor necrosis factor-a, interleukin-6, and other members of the IL-6 protein family. The transcription factors activated by these signaling mechanisms have traditionally been considered "undruggable." However, recent experimental evidence indicates that inhibition of transcription factor synthesis and/or activation may be achieved which could be employed to suppress MMP gene activity.