Matrix Metalloproteinase-10 (MMP-10) Interaction with Tissue Inhibitors of Metalloproteinases TIMP-1 and TIMP-2

Batra, Jyotica; Robinson, James C.; Soares, Alexei S.; Fields, Alan P.; Radisky, Derek C.; Radisky, Evette S.

doi:10.1074/jbc.m112.341156

Cited by 100 publications

(118 citation statements)

References 86 publications

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“…43 Also, while TIMP-1 and TIMP-2 bind MMP-10 (stromelysin-2), the binding is 10-fold weaker than that to MMP-3 (stromelysin-1). 44 TIMP-1 has a threonine-2 (Thr2) residue that interacts with the MMP S1’ pocket in a manner similar to that of a substrate P1’ substituent, largely determining the affinity to MMP-3. Substitutions at Thr2 affect the stability of the TIMP-MMP complex and the TIMP specificity to different MMPs.…”

Section: Tissue Inhibitors Of Metalloproteinases (Timps)mentioning

confidence: 99%

Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders

Liu

Khalil

2017

Progress in Molecular Biology and Translational Science

118

161

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Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic enzymes that degrade various proteins in the extracellular matrix (ECM). MMPs may also regulate the activity of membrane receptors and post-receptor signaling mechanisms, and thereby affect cell function. The MMP family includes collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs and other MMPs. Inactive proMMPs are cleaved by other MMPs or proteases into active MMPs, which interact with various protein substrates in ECM and cell surface. MMPs regulate important biological processes such as vascular remodeling and angiogenesis, and may be involved in the pathogenesis of cardiovascular disorders such as hypertension, atherosclerosis, and aneurysm. The role of MMPs is often assessed by measuring their mRNA expression, protein levels, and proteolytic activity using gel zymography. MMP inhibitors are also used to assess the role of MMPs in different biological processes and pathological conditions. MMP activity is regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), and the MMP/TIMP balance could determine the net MMP activity, ECM turnover, and tissue remodeling. Also, several synthetic MMP inhibitors have been developed. Synthetic MMP inhibitors include a large number of zinc binding globulins (ZBGs), in addition to non-ZBGs and mechanism-based inhibitors. MMP inhibitors have been proposed as potential tools in the management of osteoarthritis, cancer, and cardiovascular disorders. However, most MMP inhibitors have broad-spectrum actions on multiple MMPs and could cause undesirable musculoskeletal side effects. Currently, doxycycline is the only MMP inhibitor approved by the Food and Drug Administration. New generation biological and synthetic MMP inhibitors may show greater MMP specificity and fewer side-effects, and could be useful in targeting specific MMPs, reducing unrestrained tissue remodeling, and the management of MMP-related pathological disorders.

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Section: Tissue Inhibitors Of Metalloproteinases (Timps)mentioning

confidence: 99%

Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders

Liu

Khalil

2017

Progress in Molecular Biology and Translational Science

118

161

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“…For example, whereas TIMP-2 and -3 can inhibit MT1-MMP and MT2-MMP, TIMP-1 is a poor inhibitor of MT1-MMP, MT3-MMP, MT5-MMP, and MMP-19 (Baker et al, 2002). Also, the binding of TIMP-1 and -2 to MMP-10 (stromelysin-2) is 10-fold weaker than their binding to MMP-3 (stromelysin-1) (Batra et al, 2012). TIMP-1 has a Thr2 residue that interacts with the specific P19 substituent of MMP-3, and substitutions at Thr2 affect the stability of the TIMP-MMP complex and the specificity for different MMPs.…”

Section: Timps and Timp/mmp Ratiomentioning

confidence: 99%

Matrix Metalloproteinases as Regulators of Vein Structure and Function: Implications in Chronic Venous Disease

MacColl

Khalil

2015

J Pharmacol Exp Ther

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Lower-extremity veins have efficient wall structure and function and competent valves that permit upward movement of deoxygenated blood toward the heart against hydrostatic venous pressure. Matrix metalloproteinases (MMPs) play an important role in maintaining vein wall structure and function. MMPs are zinc-binding endopeptidases secreted as inactive pro-MMPs by fibroblasts, vascular smooth muscle (VSM), and leukocytes. ProMMPs are activated by various activators including other MMPs and proteinases. MMPs cause degradation of extracellular matrix (ECM) proteins such as collagen and elastin, and could have additional effects on the endothelium, as well as VSM cell migration, proliferation, Ca 21 signaling, and contraction. Increased lower-extremity hydrostatic venous pressure is thought to induce hypoxia-inducible factors and other MMP inducers/ activators such as extracellular matrix metalloproteinase inducer, prostanoids, chymase, and hormones, leading to increased MMP expression/activity, ECM degradation, VSM relaxation, and venous dilation. Leukocyte infiltration and inflammation of the vein wall cause further increases in MMPs, vein wall dilation, valve degradation, and different clinical stages of chronic venous disease (CVD), including varicose veins (VVs). VVs are characterized by ECM imbalance, incompetent valves, venous reflux, wall dilation, and tortuosity. VVs often show increased MMP levels, but may show no change or decreased levels, depending on the VV region (atrophic regions with little ECM versus hypertrophic regions with abundant ECM) and MMP form (inactive pro-MMP versus active MMP). Management of VVs includes compression stockings, venotonics, and surgical obliteration or removal. Because these approaches do not treat the causes of VVs, alternative methods are being developed. In addition to endogenous tissue inhibitors of MMPs, synthetic MMP inhibitors have been developed, and their effects in the treatment of VVs need to be examined.

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“…109 Also, while TIMP-1 and -2 can bind MMP-10 (stromelysin-2), their binding is 10-fold weaker than that to MMP-3 (stromelysin-1). 110 Importantly, TIMP-1 has a threonine-2 (Thr2) side chain that enters the MMP S1′ pocket in a manner similar to that of a substrate P1′ substituent, largely determining the affinity to MMP-3. Substitutions at Thr2 could affect the stability of the TIMP-MMP complex and the TIMP specificity for different MMPs.…”

Section: Potential Benefits Of Mmp Inhibitors In Vvsmentioning

confidence: 99%

Matrix Metalloproteinases in Remodeling of Lower Extremity Veins and Chronic Venous Disease

Chen

Peng

Raffetto

et al. 2017

Progress in Molecular Biology and Translational Science

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The veins of the lower extremity are equipped with efficient wall, contractile venous smooth muscle (VSM) and competent valves in order to withstand the high venous hydrostatic pressure in the lower limb and allow unidirectional movement of deoxygenated blood towards the heart. The vein wall structure and function are in part regulated by matrix metalloproteinases (MMPs). MMPs are zinc-dependent endopeptidases that are secreted as inactive proMMPs by different cells in the venous wall including fibroblasts, VSM and leukocytes. ProMMPs are activated by other MMPs, proteinases, and other endogenous and exogenous activators. MMPs degrades various extracellular matrix (ECM) proteins including collagen and elastin, and could affect other cellular processes including endothelium-mediated dilation, VSM cell migration and proliferation as well as modulation of Ca2+ signaling and contraction in VSM. It is thought that increased lower limb venous hydrostatic pressure increases hypoxia inducible factors and other MMP inducers such as EMMPRIN, leading to increased MMP expression/activity, ECM protein degradation, vein wall relaxation, and venous dilation. Vein wall inflammation and leukocyte infiltration cause additional increases in MMPs, and further vein wall dilation and valve degradation, that could lead to chronic venous disease and varicose veins (VVs). VVs are often presented as vein wall dilation and tortuosity, incompetent venous valves and venous reflux. Different regions of VVs show different MMP levels and ECM proteins with atrophic regions showing high MMP levels/activity and little ECM compared to hypertrophic regions with little or inactive MMPs and abundant ECM. Treatment of VVs includes compression stockings, venotonics, sclerotherapy or surgical removal. However, these approaches do not treat the cause of VVs, and other lines of treatment may be needed. Modulation of endogenous tissue inhibitors of metalloproteinases (TIMPs), and exogenous synthetic MMP inhibitors may provide new approaches in the management of VVs.

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Matrix Metalloproteinase-10 (MMP-10) Interaction with Tissue Inhibitors of Metalloproteinases TIMP-1 and TIMP-2

Cited by 100 publications

References 86 publications

Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders

Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders

Matrix Metalloproteinases as Regulators of Vein Structure and Function: Implications in Chronic Venous Disease

Matrix Metalloproteinases in Remodeling of Lower Extremity Veins and Chronic Venous Disease

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