Matrix metalloproteinaes and bone metastasis.

Abstract

The degradation of stromal and epithelial extracellular matrices (ECM) is partly mediated by a family of zinc-dependent endopeptidases, the matrix metalloproteinases (MMPs), which have the potential to cleave virtually all structural ECM components and thus are major mediators of extracellular proteolysis in normal and pathological conditions. In humans, the MMP family comprises at least 25 closely homologous multidomain enzymes that share common structural and functional features. Overall, the MMP family has evolved to include both secreted and plasma membrane-tethered members, thus conferring the MMPs with the ability to mediate proteolytic events at both the cell surface and in the immediate peri-cellular milieu. With few exceptions, MMPs comprise four basic domains: a signal peptide, a propeptide domain, a catalytic domain and a C-terminal domain known as the hemopexin-like domain. The propeptide domain is a short stretch of residues containing the conserved PRCG(V/N)PD, which maintains the enzyme in its inactive, zymogen state (referred here as pro-MMP) until its proteolytic removal, via the so-called “cysteine switch” (Nagase, 1999). A cysteine residue within the propeptide domain occupies a coordination site of the catalytic zinc to maintain enzyme latency (Becker et al., 1995; Van Wart and Birkedal-Hansen, 1990). The catalytic domain of MMPs contains two zinc ions, which are important for either structural or catalytic competence, and at least one calcium ion. The catalytic zinc ion is coordinated to three histidine residues, and it is necessary for MMP proteolytic activity (Bode et al, 1994; Salowe et al., 1992). All MMPs, except MMP-7 and MMP-26, contain a hemopexin-like domain, which is connected to the catalytic domain via a hinge region. Depending on the type of MMP, the hemopexin-like domain plays a role in substrate binding and interactions with tissue inhibitors of metalloproteinases (TIMPs), which affect MMP substrate recognition, zymogen activation and inhibition of activity. Structurally, the hemopexin-like domain has an ellipsoid shape, composed of a four-bladed ß -propeller structure (). In the case of the zymogenic form of the gelatinases, the hemopexin-like domain can bind TIMPs, a family of endogenous MMP inhibitors, with proMMP-2 binding TIMP-2, TIMP-3, and TIMP-4 and pro-MMP-9 binding TIMP-1 and TIMP-3 (Baker et al., 2002). For a long time, the significance of the binding of TIMPs to the latent form of the gelatinases was not understood because the zymogens are devoid of enzymatic activity. It turned out that in the case of pro-MMP-2, binding of TIMP-2 plays a role in zymogen activation by MT-MMPs (described below).KeywordsVascular Endothelial Growth FactorBone MetastasisBone Marrow Stromal CellSkeletal MetastasisNational Academy ofSciencesThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.