Matrix metalloproteinases

Details Matrix metalloproteinases Matrix metalloproteinases

2001-05-22

2004-05-11

Prouty, Rebecca E. (Department: 1652)

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

Hydrolase

C435S252300, C435S320100, C435S252330, C435S348000, C435S325000, C435S254200, C435S254210, C435S358000, C435S357000, C435S367000, C435S364000, C435S369000, C435S091500, C435S023000

Reexamination Certificate

active

06734005

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to the fields of genetics and cellular and molecular biology. More particularly, the invention relates to novel matrix metalloproteinases.
BACKGROUND OF THE INVENTION
Matrix metalloproteinases (MMPs; matrixins) comprise a family of structurally related Zn-containing proteases that degrade all macromolecules present in the extracellular matrix (ECM). Each of the known MMPs can be divided up into a variable number of well-conserved domains. All contain a pro-peptide which is involved in suppressing the activity of the pro-enzyme form of the molecule, and a HEXXH sequence motif that has been shown by X-ray crystallography to form part of the metal-binding site (Nagase et al. (1999) J. Biol. Chem., 274, 31, 21491-21494). In addition, fibronectin-, hemopexin-, or vitronectin-like domains and/or a membrane “anchor” domain may also be present.
Today, the MMP family includes more than 15 members (Table 1).
TABLE 1
Characteristics of known human MMPs
MMP
Type
Substrate
MMP-1
Collagenase
collagen I, II, III, VII, X gelatins
MMP-2
Gelatinase B
collagens IV, V, VII, XI, fibronectin, elastin
MMP-3
Stromelysin 1
proteoglycans, gelatins, fibronectin,
collagens II, IV, IX
MMP-7
Matrilysin
Proteoglycans, gelatins, collagen TV, elastin
MMP-8
Neutrophil
collagens I, II, III
collagenase
MMP-9
Gelatinase B
gelatins, collagen IV, V,
proteoglycan, elastin
MMP-10
Stromelysin 2
proteoglycan, fibronectin, laminin
MMP-12
Macrophage
proteoglycans, elastase
elastase
MMP-13
Collagenase 3
collagens I, II, III, IV
MMPs are believed to play a critical role in many physiological and pathological processes. The breakdown of ECM by MMPs is essential for processes including embryonic development, morphogenesis, reproduction, and tissue repair and remodeling. Other physiological processes which involve MMPs include tumor growth, tumor invasion, Sjögren's syndrome, periodontal diseases, arthritis, cardiomyopathy, renal failure, atherosclerosis, insulin resistance, adipogenesis, retinal neovascularization, wound healing, and neurodegenerative diseases including, for example, Alzheimer's disease, multiple sclerosis, Parkinson's disease, and motoneuron disease. Identification of the functions of additional genes of the MMP family would be invaluable to those of skill in the art seeking to understand the genetic basis for these processes, as well as identifying compounds that modulate the activity of such genes useful in methods for treating the pathologies.
Tissue inhibitors of metalloproteinases (TIMPs) are a group of closely related secreted proteins that limit MMP activity. To date, four TIMPs have been characterized; TIMP1, TIMP2, TIMP3, and TIMP4, respectively (Gomez et al. (1997) Eur. J. Cell. Biol., 74, 111-122). Several investigators have studied effects of MMP inhibition by using cells over-expressing TIMPs. The balance between MMPs and TIMPs seems to play an important role in matrix turnover in several organ systems.
The past few years have witnessed several advances in the understanding of the pathophysiology of coronary atherosclerosis. The earliest atherosclerotic lesion, named the fatty streak, represents a dynamic balance of the entry and exit of lipoprotein as well as the development of extracellular matrix. A decrease in lipoprotein entry will probably result in a predominance of lipoprotein exit and final scarring. However, an increase of lipoprotein entry can predominate over the efflux and scarring, resulting in vulnerable lipid-rich plaques that are prone to disruption (Falk et al., (1995), Circulation, 92:657-671; Fuster et al., (1999), Lancet, 353:SII: 5-9).
It is evident from many studies that MMPs, as a family, are important regulators of atherosclerotic plaque growth (Newby et al., (1994), Basic Res. Cardiol. 89 [Suppl. 1] 59-70). However, the roles of the individual MMPs are so far largely unknown. Several MMPs are expressed in the diseased blood vessel, i.e. in smooth muscle cells and in macrophages. MMPs likely regulate both the degradation of extracellular matrix and influence the proliferation rate of smooth muscle cells. Several inflammatory cytokines and growth factors increase the expression of MMPs in cell cultures, e.g. interleukin-1, platelet-derived growth factor (PDGF) and tumor necrosis factor-&agr; (TNF-&agr;).
It has been demonstrated in several animal models that inhibition of MMPs (type 1 and 2 among others) decreases smooth muscle proliferation in response to vascular damage. Moreover, MMPs seem to enhance smooth muscle cell migration. These two physiological processes are hallmarks of the neointimal thickening that characterizes atherosclerosis. Accordingly, MMP inhibitors may delay or prevent spontaneous atherogenesis as well as restenosis. MMPs and/or TIMPs may be especially useful for patients at risk for atherosclerosis, dyslipidemia, end-stage renal failure, or patients who have undergone Percutaneous Transluminal Coronary Angioplasty Procedure (PTCA).
A large number of studies support a role of MMPs in intima media function. For example, over-expression of TIMP2 inhibits vascular smooth muscle cell proliferation and chemotaxis in vitro (Baker et al., (1998), J. Clin. Invest., 101:1478-1487; Cheng et al., (1998), Circulation, 98:2195-2201). In addition, it has been shown that MMPs are linked to the proliferation and outgrowth of vascular smooth muscle cells from explants of rabbit aorta in vitro. The proliferation and outgrowth of vascular smooth muscle cells from rabbit aorta was blocked by experimental inhibitors (Ro 31-4724 and Ro 31-7467) (Newby et al., (1994). Batimastat (BB94), a synthetic MMP inhibitor, can reduce smooth muscle cell proliferation in vitro as well as inhibit neointimal formation after balloon injury to the rat carotid artery (Zempo et al., (1996), Artherioscler. Thromb. Vasc. Biol., 16:28-33). Local overexpression of TIMP1 has been shown to inhibit intimal hyperplasia in rats (Forough et al., (1996), Circ. Res., 79:812-820). After in vitro incubation with MMP-3, -7, or -12, the ability of HDL(3) to induce the high affinity component of cholesterol efflux from the macrophage foam cells was strongly reduced (Lindstedt et al., (1999), J. Biol. Chem., 274:22627-22634).
Angiogenesis, also known as neovascularization or new vessel growth, is part of the normal wound healing machinery and can occur as a reaction to tissue hypoxia. Various tumors are also known to trigger angiogenesis, leading to tumor growth. In normal adult tissue, there is a balance between angiogenic and anti-angiogenic factors and, as a result, few new vessels are formed. However, if the balance between angiogenic and anti-angiogenic factors is disturbed, a complex cascade of events can be triggered that eventually leads to the formation of new blood vessels.
Diabetic retinopathy is the leading cause of blindness for the majority of Americans. Microvascular damage from diabetes leads to microaneurysms, hemorrhage, exudates, and cotton-wool spots. Further progression of disease leads to neovascularization. Growth of new blood vessels can cause severe hemorrhage, scarring, and permanent visual loss (for a review, see Frank et al, (1996), South. Med. J., 89:463-470; Jampol & Goldbaum, (1980), Surv. Ophthalmol. 25:1-14). Various randomized, prospective studies have clearly shown benefit from laser therapy at specific stages of progression of retinopathy.
AMD with rapid progression (wet AMD) is another common cause of blindness in the developed world. Presently the underlying etiology of AMD is unknown but a slow deterioration of the retinal pigment epithelium, leading to the death of macular photoreceptors, is believed to be an important factor. The wet form of AMD often leads to a complete loss of central vision within a few years. AMD usually debuts in the dry form and may subsequently change into the wet form. AMD with rapid progression is characterized by choroidal new vessel formation (CNV). The new vessels tend to leak and may rupture. The resulting macular edema, bleeding, fibrinous deposits

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