Developmental and homeostatic remodeling of the extracellular matrix (ECM) is a highly regulated process orchestrated by a family of zinc-containing, calcium-dependent neutral proteases known as the matrix metallo-proteinases (MMP). This family of enzymes, which now contains twenty members, can collectively degrade all structural proteins of the ECM including interstitial collagens (I, II, III, and V), basement membrane collagens (IV), fibronectin, laminin, proteoglycan, and elastin (Table 1 ). The enzymatic activity of MMP family members is controlled by a group of inhibitor proteins known as the Tissue Inhibitors of Metalloproteinases (TIMPs), which consist of four family members (Table 2 ). Whereas all four TIMPs can inhibit all MMPs in vitro, preferential TIMP-MMP interactions and tissue-restricted TIMP expression suggest that each TIMP has a specific function (Table 2 ). Table 1The Matrix Metalloproteinases (MMPs)
|
MMP-1 |
Collagenase-1 |
Collagens I, II, III, VI, X, gelatins, aggrecan, entactin |
(154–158) |
|
MMP-2 |
72 kDa Gelatinase, Gelatinase A |
Gelatins, collagens I,IV, V, VII, X, XI, fibronectin, laminin, aggrecan, elastin, large tenascin C, vitronectin, β-amyloid protein precursor |
(157–159) |
|
MMP-3 |
Stromelysin-1 |
Aggrecan, gelatins, fibronectin, laminin, collagen III, IV, IX, X, large tenascin C, vitronectin |
(28,157,158,160,161) |
|
MMP-7 |
Matrilysin, Pump |
Aggrecan, fibronectin, laminin, collagen IV, elastin, entactin, small tenascin C, vitronectin |
(157,158,162,163) |
|
MMP-8 |
Collagenase-2, Neutrophil Collagenase |
Collagens I, II, III, aggrecan |
(157,158,164) |
|
MMP-9 |
92 kDa Gelatinase, Gelatinase B |
Gelatins, collagens IV, V, XIV, aggrecan, elastin, entactin, vitronectin |
(157,158,165,166) |
|
MMP-10 |
Stromelysin-2 |
Aggrecan, fibronectin, laminin, collagen IV |
(157,158,167) |
|
MMP-11 |
Stromelysin-3 |
Fibronectin, laminin, collagen IV, aggrecan, gelatins |
(141,158) |
|
MMP-12 |
Metalloelastase |
Elastin |
(147,158) |
|
MMP-13 |
Collagenase-3 |
Collagens I, II, III |
(88,89,124,158,168,169) |
|
MMP-14 |
Membrane-type-1 -MMP |
Collagens I, II, III, fibronectin, laminin, vitronectin, proteoglycan, ProMMP-2, ProMMP-13 |
(158,170) |
|
MMP-15 |
Membrane-type-2-MMP |
Not known |
(158,171) |
|
MMP-16 |
Membrane-type-3-MMP |
ProMMP-2 |
(158,172) |
|
MMP-17 |
Membrane-type-4-MMP |
Not known |
(158,173) |
|
MMP-18 |
Collagenase-4,XenopusCollagenase |
Collagen I |
(158,174,175) |
|
MMP-19 |
Not Known |
(158,176,177) |
|
|
MMP-20 |
Enamelysin |
Amelogenin (The major tooth enamel matrix protein) |
(178) |
Table 2Tissue Inhibitors of Metalloproteinases (TIMPs)
|
TIMP-1 |
Inhibition of all known MMP family members. Associates with proMMP-9. Inhibits angiogenesis. Erythroid-potentiating actvity. |
(179–181) |
|
TIMP-2 |
Inhibitions all known MMP family members. Associates with MT1-MMP and MMP-2 at cell surface and regulates MMP-2 activation. |
(181–184) |
|
TIMP-3 |
Inhibition of all known MMP family members. Extracellular matrix-associated. Mutation associated with Sorsby's fundus dystrophy. |
(55,181,185–188) |
|
TIMP-4 |
Inhibition of all known MMP family members. Restricted expression suggests tissue specific TIMP function. |
(181,189,190) |
