mmp in periodontics

8/11/2019 MMP in periodontics

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By,Prarthana.Pai

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Matrix Metalloproteinases


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CONTENTS

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Introduction

Structure

Classification

Individual MMPs Regulation of activation of MMPs

Activation of Pro-MMPs

Inhibitors of MMPs

MMPs and periodontal disease Conclusion

References


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Introduction

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Extracellular matrix (ECM) macromolecules are important for

creating the cellular environments required during

development and morphogenesis.

Matrix Metalloproteinases (MMPs), collectively called

Matrixins, is a large family of calcium-dependent zinc-

containing endopeptidases, that participate in ECM

degradation.

Under normal physiological conditions, the activities of MMPs

are precisely regulated at the level of:

Transcription

Activation of the precursor zymogens

Interaction with specific ECM components


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A loss of activity control may result in diseases such

as arthritis, cancer, atherosclerosis, aneurysms,nephritis, tissue ulcers, periodontal destruction and

fibrosis.

MMPs are excreted by a variety of connective tissue

and pro-inflammatory cells including fibroblasts,

osteoblasts, endothelial cells, macrophages,

neutrophils, and lymphocytes.

These enzymes are expressed as zymogens, which

are subsequently processed by other proteolytic

enzymes to generate the active forms.


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The various physiological and pathological processes for whichMMPs have been implicated are:


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History

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The earliest descriptions of MMPs were in 1949 asdepolymerizing enzymes which, it was proposed,

could facilitate tumor growth by making connective

tissue stroma, including that of small blood vessels,

more fluid.

About after 13 years, in 1962 Jerome Gross andCharles Lapire found an active enzyme in the

culture media of tissue fragments of tail fin skin that

degraded the triple helix of native type I collagen.


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During the next 20 years, several mammalian

enzymes were partially purified, but it was not until

1985 that the field really developed when structural

homologies became apparent, allowing many newmembers to be identified through the techniques of

molecular biology.

Since then, at least 26 human MMPs have been

characterized.


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Structure of MMPs

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The MMPs starting from the Nterminus, show the

following features: Massova et al., 1998

Signal peptide

Propeptide Furin-cleavage site insert

Catalytic domain

Fibronectin-like repeats

Hinge region Hemopexin domain

Membrane insertion extension


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Signal peptide:

It is typically a stretch of 17 to 20 residues, rich in

hydrophobic amino acids, that serves as a signal forsecretion into the endoplasmic reticulum for eventual

export from the cell.


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Propeptide domain:

It consists of approximately 80 to 90 amino acids

containing a cysteine residue, which interacts with thecatalytic zinc atom via its side chain thiol group.

A highly conserved sequence is present in the

propeptide.


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Removal of the propeptide by proteolysis results in

proenzyme activation, as all members of the MMPs familyare produced in a latent form.

The Cys within this sequence (the cysteine switch)

ligates the catalytic zinc to maintain the latency of pro-MMPs

Borden and Heller, 1997

This cysteine is found in all MMPs, including those that

have the furin-cleavage site.


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Furin-cleavage site insert:

This stretch of about nine residues includes the consensussequence of RXKR/RRKR that leads to intracellular cleavageby furin.

MMP-11, -14,-15, -16, and-17 possess this sequence


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In the remaining enzymes, a cleavage by externalproteases occurs in the middle of the propeptide,

partially exposing the zinc and leading to autolytic

cleavage of the remainder of the propeptide.

The exact site of final cleavage may vary within a given

enzyme leading to different degrees of activation,particularly in the case of MMP-1.


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The catalytic domain:

It is made of about 170 amino acids.

It contains two zinc ions and at least one calcium ion

coordinated to various residues.


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One of the two zinc ions is present in the active site andis involved in the catalytic processes of the MMPs.

The catalytic zinc ion is essential for the proteolyticactivity of MMPs; the three histidine residues thatcoordinate with the catalytic zinc are conserved among

all the MMPs.

The 50 to 54 residues at the C-terminal end of thecatalytic domain include the site of binding of the

catalytic zinc.

Little is known about the roles of the second zinc ion andthe calcium ion within the catalytic domain, but the

MMPs are shown to possess high affinities for structuralzinc and calcium ions (Bode et al., 1994).


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Fibronectin-like repeats:

These specialized structures aid the binding of enzyme

to gelatin and collagen substrates

Steffensen et al., 1995


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Hinge region:

The catalytic domain is connected to the following

hemopexin domain by a linker region usually referred to

as the hinge region.

It ranges in length from 0 to 75 residues.


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The longest hinge is found in MMP-9 and shows

considerable homology to type V collagen in that it is rich

in proline.

A typical hinge contains about 16 residues including a

number of proline residues

Pendas et al., 1997


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The hemopexin-like domain:

It is made up of about 210 amino acids.

It is highly conserved and shows sequence similarity to

the plasma protein, hemopexin.


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The hemopexin-like domain has been shown to play a

functional role in substrate binding and/or in interactionswith the TIMPs, a family of specific MMP protein

inhibitors

Gomis-Rth et al., 1997

The hemopexin domain is an absolute requirement for

collagenases to cleave triple helical interstitial collagens(Bode, 1995), although the catalytic domains alone

retain proteolytic activity toward other substrates.


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Membrane insertion extension:

Although most MMPs have their C terminus at the end of

the hemopexin domain, the four MT-MMPs have a further

extension that governs insertion of these proteases into

the cell membrane.

Its length ranges from about 80 to 110 residues.


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Classification

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According to their substrate specificity, sequence similarity,

and domain organization (Massova et al.,1998)

Collagenases (MMP-1, 8, 13 and 18)Gelatinases (MMP-2 and 9)

Stromelysins (MMP-3, 10, 11)

Elastases (MMP-7 and 12), and

Membrane type MMP (MT-mmps, MMP-14, 15,

16 and 17)

Other MMPs


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Individual MMPs

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Collagenases

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MMP-1, MMP-8, MMP-13, and MMP-18 (Xenopus) are in

this group.

The key feature of these enzymes is their ability to

cleave interstitial collagens I, II, and III at a specific sitethree-fourths from the N-terminus.


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Collagenases can also digest a number of other ECM

and non-ECM molecules

Collagenases are actively taking part in the tissue

destruction and granulation tissue formation in chronicperiodontitis

Wahlgren, 2003

The collagenases differ in their substrate specificities

and functional roles.


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MMP 1

Interstitial collagenase/ collagenase 1

Most often associated collagenase with normal tissueremodeling

Expressed by fibroblasts, endothelial cells, macrophages,

hepatocytes,chondrocytes, osteoblasts, odontoclasts,

tumors cells and migrating epidermal keratinocytes.


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Expression can be induced in certain inflammatory

diseases and cancers

Giambernardi et al., 1998

MMP-1 gene is localized on chromosome 11q22

Brinckerhoff et al., 2000

It is constitutively expressed at low levels under normal

physiological conditions & its expression may increase

markedly in pathological conditions.


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MMP-8

It was first cloned from messenger RNA (mRNA)

extracted from the peripheral leucocytes of a patient with

chronic granulocytic leukemia

Hasty et al., 1990

Synthesized in polymorphonuclear leukocytes during their

maturation in bone marrow and stored in specific

intracellular granules, out of which it is secreted to the cellenvironment in response to external triggering stimuli and

the enzyme thus plays a key role in tissue destruction

during inflammatory diseases

Ding et al., 1997


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In periodontitis, the MMP-8 is expressed in variousinflammatory cells, such as PMNs, macrophages, plasma

cells and in endothelial cells.

In pulpitis, MMP-8 it is considered to originate from both

PMN and non-PMN lineage cells.

Wahlgren, 2003


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The major collagenase species detected in inflamedhuman periodontium is MMP-8

Romanelli et al., 1999

MMP-8 is expressed in vivo by:-o

Bronchial epithelial cells and macrophages involved inbronchiectasis,

o Chondrocytes in rheumatoid arthritis and osteoarthriticlesions

o Fibroblasts in human gingival sulcular epithelial cells

o Cells of human atheromao Plasma cells associated with oral keratocysts

o Cells in proliferating and migratory wound epithelia, indermal fibroblasts and inflammatory cells

Tervahartiala et al., 2000


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MMP-13

Originally cloned from human breast tumor cDNA library

by Hasty et al., 1990

It has the widest substrate selection among the interstitialcollagenases and, in addition to collagens, it is able to

cleave various Basement Membrane components.

MMP-13 cleaves type II collagen more efficiently thantypes I and III, and among interstitial collagenases, it is

most effective in cleaving gelatin (Ding et al., 1997).


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Gelatinases

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Gelatinase A (MMP-2) and gelatinase B (MMP-9) belongto this group

They readily digest the denatured collagens, gelatins.

These enzymes have three repeats of a type II

fibronectin domain inserted in the catalytic domain, which

bind to gelatin, collagens, and laminin.


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MMP-2, but not MMP-9, digests type I, II, and III

collagens.

Although MMP-2 null mice develop without any

apparent abnormality, mutations in human MMP-2

resulting in the absence of active enzyme are linkedwith an autosomal recessive form of multicentric

osteolysis, a rare genetic disorder that causes

destruction and resorption of the affected bones.

Martignetti JA, 2000

This suggests that MMP-2 in humans is important for

osteogenesis.


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Stromelysins

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Stromelysin 1 (MMP-3) and stromelysin 2 (MMP-10) bothhave similar substrate specificities, but MMP-3 has a

proteolytic efficiency higher than that of MMP-10 in

general.


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Besides digesting ECM components, MMP-3 activates anumber of proMMPs, and its action on a partially

processed proMMP-1 is critical for the generation of fully

active MMP-1.

MMP-11 is called stromelysin 3, but it is usually groupedwith otherMMPsbecause the sequence and substrate

specificity diverge from those of MMP-3


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ECM components, MMP-7 processes cell surface

molecules such as pro-defensin, Fas-ligand, protumor

necrosis factor (TNF)-, and E-cadherin.

Matrilysin 2 (MMP-26) also digests a number of ECM

components.


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Membrane-Type MMPs

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There are six membrane-type MMPs (MT-MMPs)

Four are type I transmembrane proteins (MMP-14,

MMP-15, MMP- 16, and MMP-24)


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Two are glycosylphosphatidylinositol (GPI) anchored

proteins (MMP-17 and MMP-25).


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With the exception of MT4-MMP, they are all capable of

activating proMMP-2.

These enzymes can also digest a number of ECM

molecules, and MT1-MMP has collagenolytic activity ontype I, II, and III collagens.

MT1-MMP null mice exhibit skeletal abnormalities during

postnatal development that are most likely due to lack ofcollagenolytic activity.

It also plays an important role in angiogenesis.


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MT5- MMP is brain specific and is mainly expressed in

the cerebellum.

MT6-MMP (MMP-25) is expressed almost exclusively in

peripheral blood leukocytes and in anaplastic

astrocytomas and glioblastomas but not in meningiomas


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Enamelysin (MMP-20), which digests amelogenin, is

primarily located within newly formed tooth enamel.

Amelogenin imperfecta, a genetic disorder caused by

defective enamel formation, is due to mutations at MMP-

20 cleavage sites.

MMP-22 was first cloned from chicken fibroblasts, and a

human homologue has been identified on the basis of

EST sequences. The function of this enzyme is notknown.

MMP-23, also called cysteine array MMP, is mainlyex ressed in re roductive tissues.


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The enzyme lacks the cysteine switch motif in the

prodomain.

It also lacks the hemopexin domain; instead, it has acysteine-rich domain followed by an immunoglobulin-like

domain.

It is proposed to be a type II membrane protein harboring

the transmembrane domain in the N-terminal part of the

propeptide.


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Regulation of activity of MMPs

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The activity of MMPs is regulated at several different

stages:

By transcriptional regulation of MMP genes -

endogenous growth factors and cytokines

By precursor activation Disruption of cysteine-

Zn++bond.

By differences in substrate specificity

By MMP inhibitors -macroglobulin and TIMPs-

1&2.


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Activation of precursors Transcriptional Regulationof MMP genes

Differences in substrate

specificity MMP inhibitors

MMPActivity


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Activation of ProMMPs

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MMPs can be activated by proteinases or in vitro by

chemical agents, such as thiol-modifying agents (4-aminophenylmercuric acetate, HgCl2, and N-

ethylmaleimide), oxidized glutathione, SDS, chaotropic

agents, and reactive oxygens.

Low pH and heat treatment can also lead to activation.

These agents most likely work through the disturbance of

the cysteine-zinc interaction of the cysteine switch.


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Latency of the virgin enzyme is maintained, at least in

part, by virtue of a putative Cys-Zn2+ bond that links the

unpaired propeptide Cys residue to the active site Zn2+and displaces the H2O molecule, which is necesssary for

catalysis.

Springman et al., 1990; Van Wart and Birkedal- Hansen,

1990


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Organomercurials, metal ions, thiol reagents, and

oxidants presumably interact directly with the propeptide

cys-residue to shift the equilibrium between the "closed"

and the "open" form toward the open form

Chaotropic agents (3M KI, 3M nascn) and detergents (1to 2% SDS) induce polypeptide chain conformational

changes that also shift the equilibrium entirely toward the

open form.

Proteolytic enzymes excise a portion of the propepeptide

so that the switch opens, most likely because of an

entro effect.


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Proteolytic activation of MMPs is stepwise.

The initial proteolytic attack occurs at an exposed loopregion between the first and the second helices of the

propeptide.

Th l ifi it f th b it i i di t t d b


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The cleavage specificity of the bait region is dictated by

the sequence found in each MMP.

Once a part of the propeptide is removed, this probably

destabilizes the rest of the propeptide, including the

cysteine switchzinc interaction, which allows the

intermolecular processing by partially activated MMP

intermediates or other active MMPs.

Activation of proMMPs by plasmin is a relevant pathway in


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Activation of proMMPs by plasminis a relevant pathway in

vivo.

Plasmin is generated from plasminogen by tissueplasminogen activator bound to fibrin and urokinase

plasminogen activator bound to a specific cell surface

receptor.

Both plasminogen and urokinase plasminogen activator

are membrane-associated, thereby creating localized

proMMP activation and subsequent ECM turnover.

Plasmin has been reported to activate proMMP-1,

proMMP-3, proMMP-7, proMMP-9, proMMP-10, and

proMMP-13.


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Intracellular Activation

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Most proMMPs are secreted from cells and activatedextracellularly.

Pei and Weiss first demonstrated that proMMP-11

(stromelysin 3) is activated intracellularly by furin.

ProMMP-11 possesses a furin recognition sequence,

KX(R/K)R, at the C-terminal end of the propeptide.

u vP MMP 2


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ProMMP-2

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ProMMP-2 is not readily activated by generalproteinases.

The main activation of proMMP-2 takes place on the cellsurface and is mediated by MT-MMPs.

MT1-MMPmediated activation of proMMP-2 has been

studied extensively. The unique aspect is that it requires

the assistance of TIMP-2.

ProMMP-2 forms a tight complex with TIMP-2 through their C-


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g p gterminal domains, therefore permitting the N-terminal inhibitorydomain of TIMP-2 in the complex to bind to MT1-MMP on thecell surface.

This MT1-MMPTIMP-2proMMP-2 complex is thenpresented to an adjacent free MT1-MMP for activation.

The cell surfacebound proMMP-2 is then activated by an

MT1- MMP that is free of TIMP-2.


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Major cell types of human periodontal tissues


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Major cell types of human periodontal tissues

capable of expressing unique complement of MMP

when stimulated

PMN Leukocytes

Interstitial collagenase (MMP8)

Gelatinase B (MMP9)

Keratinocytes

Fibroblast collagenase (MMP1)

Gelatinase A (MMP2)

Gelatinase B (MMP9)

Stromelysin 2 (MMP 10)


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Fibroblasts

Interstitial collagenase (MMP8)


Stromelysin 1 (MMP3)

Stromelysin 3(MMP11)

Gelatinase A (MMP2)

Matrilysin (MMP7)


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Macrophage


Stromelysin 1 (MMP3)

Gelatinase A (MMP2)

Gelatinase B (MMP9)

Endothelial Cell


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Osteoid is composed by type I collagen, proteoglycans,glycoproteins, and native types IV and IX collagens.

Osteoblast-derived collagenase (MMP-13) seems to bemain responsible for degrading the nonmineralizedosteoid layer covering bone surfaces, exposing themineralized matrix to osteoclasts.

MMP-13 (collagenase-3) is expressed in osteoblasts,periosteal cells and fibroblasts during human fetal bonedevelopment, and postnatally in bone remodeling.

Cleavage of collagen I by MMP-13 seems to be the initialstep of the entire bone resorption process.


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In chronic periodontitis MMP-8 increased

TIMP are not increased.

In LAP ( Localized Aggressive Periodontitis)

MMP-1 is increased.

Elevated levels of TIMPs are present.


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MMP Inhibitors

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Under pathological conditions associated withunbalanced MMP activities, changes of TIMP levels are

considered to be important because they directly affect

the level of MMP activity.

TIMPs have effects on cell growth and survival thatcannot always be clearly reconciled with their ability to

abrogate MMPs activity.


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TIMP-2 inhibits proMMP-2 over 10-fold more effectivelythan TIMP-1.

However, TIMP-2 has a bi-functional effect on MMP-2,since MT-MMP mediated proMMP-2 activation requires a

tiny amount of TIMP-2 to make activation progress,

whereas a greater concentration of TIMP-2 inhibits MMP-

2

Brew et al., 2000


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High levels of TIMP-3 promote apoptosis in many cell

types in vitro and in vivo (Vaalamo et al., 1997), and this

effect is associated with death receptor modulation.

TIMP-3 inhibits at least MMP-2 and MMP-9, whereas

TIMP-4 is a good inhibitor for all classes of MMPs without

remarkable preference for specific MMPs.


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The TIMP structure


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The TIMPs are wedge-shaped molecules that are

subdivided into an N-terminal part (~120 aa), mainly

consisting of a closed five-stranded b-barrel, and a C-

terminal part (~60 aa) which forms -turn structure.

The N-terminal part resembles the so-called OB-fold

known for a number of oligosaccharide/oligonucleotide-binding proteins.


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While the N-terminal part is in intimate contact with the

active site of the target MMP, the C-terminal part seems tohave only minor impact on the tightness of the interaction

with the MMP (except for the MMP2-TIMP-2 complex).

However, it conveys other functions such as the binding

of TIMP-2 to proMMP, which is an essential step in the

activation procedure of proMMP-2 and inhibition ofangiogenesis.

Inhibition mechanism of TIMPs


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Inhibition mechanism of TIMPs

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There are different mechanisms to inhibit ordownregulate MMPs.

Inhibition may take place by:

Interaction with an active zn2+ -site

By cleaving the active enzyme

By binding it to a non-active complex form.


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To influence the MMP levels, it is also possible to down-

regulate MMPs at the transcriptional level

Birkedal-Hansen et al., 1993

The proteolytic activity of the MMPs involved in

extracellular matrix degradation must be preciselyregulated by their endogenous protein inhibitors, the

TIMPs.

Disruption of this balance results in serious diseases.

-Macroglobulins


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-Macroglobulins

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-Macroglobulins inactivate susceptible proteinases by

entrapment following cleavage of the bait region.

The proteinase cleaves one or more bonds in the 40

residue bait region and thereby initiates a conformational

change that leads to entrapment of the proteinase

Sottrup-Jensen et al, 1989

a-macroglobulins play an important role in the regulation


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a-macroglobulins play an important role in the regulation

of MMP activity.

The rapid capture rates, particularly with collagenase,

render the reaction all but instantaneous.

Cawston and Mercer (1986) showed that in a mixture ofTIMP and 2M, collagenase binds preferentially to 2M.

It is also of note that the concentration of 2M in the

interstitial fluid is quite considerable and often

approaches plasma values (2.2 mg/ml)

Tollefsen and Saltvedt, 1980

2M concentrations in synovial fluids from rheumatoid


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2M concentrations in synovial fluids from rheumatoidarthritis patients range from 0.7 to 1.1 mg/ml whereasthose of osteoarthritis patients are slightly lower, 0.5 to

0.6 mg/mlVirca et al, 1982, Abe et ai, 1973

Similar determinations on gingival crevicular fluids(GCFs) from variously inflamed sites have yielded valuesfrom 0.2 to 2.4 mg/ml

Schenkein and Genco, 1977; Tollefsen and Saltvedt, 1980;

Condacci et al, 1982; Sengupta et al, 1988

These values suggest that 2M concentrations ininterstitial fluids are as much as 100- to 1000- fold greaterthan those of TIMPs

Cawston et al 1987 Ha akawa et al 1991

Inhibiting Antibodies


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Inhibiting Antibodies

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Production of blocking antibodies represents another

attractive approach to the design of effective and specific

inhibiting reagents.

Affinity purified polyclonal antibodies as well as

monoclonal antibodies are both highly effective and attain

IC50 in the 1 to 10 ug/ml range (20 to 200 nM).

The best of these are almost as potent as good synthetic


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The best of these are almost as potent as good synthetic

inhibitors and are frequently highly specific and readily

discriminate between closely related enzymes such as

FIB-CL and PMN-CL

Birkedal-Hansen etal, 1988

The inhibition obtained with monoclonal antibodies to

collagenase on collagenous substrates is virtually

complete (>90%) but similar antibodies against GLs on

gelatin substrates appear to be less effective (40 to 60%inhibition)

Hoyhtya et al, 1988; Birkedal-Hansen et al, 1992c

Synthethic inhibitors


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Synthethic inhibitors

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The development of synthetic inhibitors of MMPs has

been relied on the peptide sequence, recognized by the

targeted protease, to which have been grafted differentchemical functionalities able to interact potently with the

zinc ion of the active site.


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The requirements for a molecule to be an effective

inhibitor of the MMP class of enzymes are: Functional group [e.g., hydroxamate (CONHO--),

carboxylate (COO--), thiolate (S--), phosphinyl (PO2--) etc.]

capable of chelating the active-site zinc2+Ion (this will be

referred to as zinc binding group or ZBG)

At least one functional group that provides a hydrogen

bond interaction with the enzyme backbone

One or more side chains, which undergo effective van der

Waals interactions with the enzyme subsites.


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Natural product MMP inhibitors include tetracyclines,

pycnidione, neovastat, squalamine, genistein, nobiletin,

myricetin, curcumin, xanthorhizzol, theaflavin,resveratrol, actinonin, BE-166278 (Banyu), matlystatin B,

nicotinamide, betulinic acid, glycyrrhetinic acid,

rifampicin, catechin derivatives, and a series of

futoenone derivatives.


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Studies have demonstrated that low dose doxycycline usedas an adjunct to scaling and root planning (SRP) significantly

improves clinical attachment and reduces pocket depth,slowing the progression of periodontitis when compared withSRP alone

Caton JG, 2001

The benefits were achieved after three months of treatment,and appear to be maintained during a 3-month post-treatmentperiod

The attachment level gains in the deepest sites are modest inthese studies (~0.7 mm). The gains in deeper sites treatedwith systemic tetracyclines and SRP are twice bigger thangains achieved using MMP inhibitor.

Peterson JT. 2004

Chemically modified tetracycline's


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Chemically modified tetracycline s

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Golub and co-workers 1991, synthesized 10 differentanalogs of tetracyclines known as chemically-modified

tetracycline's (CMTs 1-10) to identify the site of the

anticollagenase property in tetracycline.

This modification, did not reduce the ability of drug to

block the activity of collagenases from a number of tissue

sources or its ability to inhibit bone resorption.

Thus, it was concluded that the C-4 moiety was not

required for the anticollagenase activity of the

tetracycline molecule.


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Investigations

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Analysis of - GCF, Serum & Saliva

Immunocytochemistry

DentoELISA

Dip stick method

CONCLUSION


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CONCLUSION

In conclusion, MMPs play an important role during the

process of periodontitis since they are responsible for thedegradation of extracellular matrix components.

In recent years the use of molecular and cellular biology

methodologies has greatly contributed to the understandingof the basic mechanisms that determine the onset andprogression of periodontal diseases.

It is likely that in a recent future they may also help in theprognosis and in the prediction of disease progression.

This will facilitate the identification of individuals at high risk

mmp in periodontics

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