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Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 2003 Nov;62(Suppl 2):ii43–ii47. doi: 10.1136/ard.62.suppl_2.ii43

Metalloproteinases, inflammation, and rheumatoid arthritis

F Mohammed, D Smookler, R Khokha
PMCID: PMC1766743  PMID: 14532148

Abstract

Ideally, the inflammatory response occurs rapidly to terminate infection. It also must halt in a timely manner to stop this reaction from inflicting self damage. Such a highly regulated process results from altering balances in pro- and anti-inflammatory signals orchestrated by multiple cell types and factors within the tissue microenvironment. The discovery of new substrates of metalloproteinases within this microenvironment has disclosed a new function in inflammation. The role of these proteases now extends beyond extracellular matrix remodelling enzymes to that of mediators of inflammatory signals involving various chemokines and cytokines. As natural inhibitors of these metalloproteinases, TIMPs have the potential of regulating the inflammatory response and affecting diseases such as rheumatoid arthritis. TIMP-3, in particular, stands out as an important regulator of inflammation with its ability to specifically inhibit proinflammatory cytokines and tissue destruction in the joint.

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Figure 1.

Figure 1

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Molecular signals involved in the generation of an inflammatory reaction. Upon injury, the host inflammatory cells respond by releasing various factors that further trigger the release of other inflammatory cues. A system of binary or higher order signals culminates in the inflammatory reaction. A role for the family of metalloproteinases is now recognised, which not only mediates tissue destruction but also generates both pro- and anti-inflammatory responses.

Figure 2.

Figure 2

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Structure of the TIMP-3 protein. TIMP-3 is glycosylated at the asparagine amino acid, N184 and contains six disulphide bonds marked by asterisks. The gray sections represent the five strands (A-E) of the N-terminus ß-barrel. Strands A and B can each strongly bind heparan sulphate, which is suggested to result from the net positive charge in these regions. They contain nine basic amino acids indicated by open circles and only one acidic residue. TIMP-1 and TIMP-2 contain several acidic residues that neutralise the charge from their basic residues residing in this region.

Figure 3.

Figure 3

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The broader inhibition profile of TIMP-3. TIMP-3 stands unique among the TIMP family of inhibitors, as it can inhibit ADAM and ADAMTS enzymes in addition to MMPs. These metalloproteinases are known to proteolytically process several factors involved in the normal inflammatory response and in inflammatory diseases.

Figure 4.

Figure 4

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The projected interactions between the metalloproteinase axis and the cytokine axis in rheumatoid disease. Metalloproteinase activity is linked to the activation of various cytokines involved in inflammation. The net metalloproteinase activity can shift the balance between some pro- and anti-inflammatory cytokines. Cytokines, in turn, also induce the production and activation of various metalloproteinases. An imbalance in one axis can potentially cause imbalance in the other perpetuating a loop of destructive activity in RA.

Selected References

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