Book Excerpt: Matrix Metalloproteinases

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flower

 

Picture a beautiful garden full of flowers. The flowers are all healthy and every petal in perfect bloom. In order to keep the garden in such great condition, the gardener tends to it every day. When flowers die, the gardener trims them off. The gardener knows that removing the dead flowers will allow for new healthy flowers to grow even better.

Matrix metalloproteinases are like the gardener in our body. When tissues are damaged or die, matrix metalloproteinases trim off the dead or damaged parts so that new, healthy tissues can grow.

Matrix metalloproteinases (MMPs) are a group of enzymes responsible for breaking down or destroying proteins, such as collagen, gelatin and proteoglycans, which are found in skin, bones, connective tissue and teeth. While it may seem like MMPs are bad because they are destroying body parts, they are, in fact, essential. Just like trimming off the dead flowers on a plant so new ones can grow better, MMPs remove parts of the body that have been damaged so that healing can take place. When damage has occurred somewhere in the body, MMPs are released and activated. The damaged tissue is then broken down and destroyed by the MMPs, so that new healthy tissue can be laid down to replace the damaged. MMPs are an important part of the healing process.

MMP = Matrix Metalloproteinase

MMP = enzyme that breaks down damaged body parts

(Matrix Metalloproteinases are also sometimes called Matrixins.)

But what if the gardener doesn’t stop picking even after all the dead flowers have been removed? Instead, the gardener continues picking off the flowers in bloom, the leaves, the stems…and soon what used to be a healthy plant is now destroyed. What started off as a healthy act for the plant, trimming dead flowers off, didn’t stop and actually caused so much damage that the plant was destroyed. Just like the gardener needs to stop picking after all the dead flowers have been removed to avoid further destruction, so too do MMPs need to be deactivated after all the damaged tissue has been removed. Without deactivation, MMPs will continue breaking down tissue, moving on to healthy tissue, resulting in damage. What started out as a healthy, healing process can became a very unhealthy, destructive process.

Deactivators of MMPs are called matrix metalloproteinase inhibitors, of which TIMPs are the most prevalent.

TIMP = Tissue Inhibitor Metalloproteinase

TIMPs are proteins that form complexes with MMPs and render them inactive. Matrix metalloproteinase inhibitors such as TIMPs, are like the gardener’s boss who tells the gardener to stop working. TIMPs maintain a balance between essential degradation, allowing for healthy regeneration and excessive degradation, resulting in damage.

Damage occurs when there is too much MMP production and/or too little TIMPs to deactivate the MMPs.

MMPs balanced by TIMPs

= Damaged tissues removed so that new tissue can grow

= Healthy healing
Excessive MMPs + Insufficient TIMPs

= Damaged tissues and healthy tissues removed

= Destruction

For example, when a wound occurs on the skin, MMPs are synthesized by both the wounded skin cells and inflammatory cells. The MMPs destroy the damaged skin by breaking it apart, and continue to destroy tissue until deactivated by TIMPs. Non-healing wounds have a higher number of MMPs and a lower number of TIMPs. Too many MMPs and not enough inhibitors of MMPs to stop their action, results in continued damage and a lack of healing.

Matrix metalloproteinases (MMPs) are involved with nearly all tissues of the body in both normal functioning and pathological events. MMPs are critical for cell growth and survival, host defence systems, tissue remodeling and development. This includes teeth and cavities.

 MMPs & Cavities

MMPs are synthesized and secreted by connective tissue cells and are found in both saliva and teeth.

In teeth, MMPs function to keep teeth healthy. Bacterial acids cause demineralization and the dissolution of hydroxyapatite – minerals are removed. This is damage that requires MMPs to clean up. The bacterial acids and demineralization is like a flower dying. MMPs are synthesized and activated and proceed to digest the demineralized, damaged dentin, and the damaged tooth tissue is removed. Damaged dentin and enamel are cleaned up to allow for tissue remodeling, regeneration and healing. MMPs stimulate growth factors necessary for reparative dentin formation, the dentin that is produced in response to cavities in an attempt to slow the rate of progression and remineralize the tooth. The highest ratio of MMPs to TIMPs is found at the junction of enamel and dentin, called the dentinoenamel junction (DEJ). This is why a cavity significantly spreads laterally once it extends through the enamel and reaches the dentin, giving dentin cavities their characteristic triangle shape, with the wide base facing out, at the DEJ, and the pointed triangle tip deep into dentin, towards the pulp.

MMPs determine how fast dentin is degraded. Like the gardener with no boss around to stop him, he will continue cutting out all the flowers and destroy the garden. When there are lots of MMPs around and few TIMPs to inactivate them, the damaged dentin will be removed, as well as the healthy dentin. This is a situation in which the cavity progresses. A healthy balance of MMPs and TIMPs however, will result in just the damaged dentin being removed so that healthy dentin can replace it, and the healing process sets in. TIMPs act like the boss, stopping the progression of a cavity.

MMPs balanced by TIMPs

= Damage caused by bacterial acids removed

= Healthy healing of tooth and cavity

 

Excessive MMPs + Insufficient TIMPs

= Damaged caused by bacterial acids and healthy dentin removed

= Cavity progression

 

Developing Teeth

MMPs play a major role in developing teeth and the production of dentin, called dentinogenesis. You can give your child an amazing life-long gift; the gift of strong, healthy teeth that will resist cavities for the rest of their life. An important way to give them this gift is by ensuring they have an ideal balance of MMPs and TIMPs so that their teeth develop optimally.

 Bacterial or Human?

Bacteria also have matrix metalloproteinases. It used to be thought that the bacterial MMPs were responsible for the destruction of dentin. However, more recent research does not support that idea.

In 1998, the Journal of Dental Research published a study of a joint effort between researchers at the University of British Columbia and the University of Helsinki.

The study looked at which enzymes were responsible for the destruction of dentin during the progression of a cavity. (Remember a cavity starts with demineralization or the removal of minerals from enamel, and then progresses to the inside part of the tooth which is dentin.)

The researchers exposed some demineralized dentin to cavity-causing bacterial MMPs and some demineralized dentin to sterilized human MMPs, containing no bacteria. Only the dentin exposed to human MMPs resulted in further degradation or progression of the cavity. The dentin exposed to the bacterial MMPs did not have any activity or breakdown at all.

Dentin in acid + Human MMPs = cavity progression

Dentin in acid + Bacterial MMPs

= no further progression

What does this mean?

After bacteria initiate a cavity in enamel, the progression of the cavity is caused by the person’s own MMPs.

Imagine someone is at a picnic. It is a beautiful day, the sun is shining, the kids are playing together peacefully and the food the person prepared is a delicious hit with everyone. Several bees are flying around the food and the person laughs and says, “Oh no bees, this is our tasty food,” and calmly covers the food up with some picnic nets. What a wonderful day.

Imagine another scene. Same person out at a picnic. But this day is rainy and cold. The kids are fighting and screaming at each other. The food is soggy from the rain and doesn’t taste very good. And then come the bees. The person angrily swats away at the bees and accidentally knocks over the dessert onto the muddy ground. Mumbling some not-so-nice words, the person picks up the ruined dessert while a bee is flying around it. Swatting at the bee again, it stings the person. Not a wonderful day.

While it may seem like the bees are responsible for the bad situation, upon closer inspection, one realizes that it cannot be the bees. The bees were the same in both situations, but the outcomes were significantly different. The outcomes were not dependent on the bees, but rather the circumstances at the picnic. Similarly, while it may seem like bacteria are responsible for the progression of a cavity, the reality is that it is the circumstances within the body that determines the extent of the damage of the cavity.

Like the bees, cavity-causing bacteria are an irritant. The cavity-causing bacteria initiate a cavity within the enamel of a tooth (the outer shell). MMPs are released to clean up the damaged tissue so that healing can take place. When MMPs are balanced by TIMPs, it is like the first picnic scenario where there are bees present but the damage caused by them is minimal. However, when there is a surplus of MMPs and a deficiency of MMP inhibitors in the body, it is like the rainy picnic with ruined food and fighting children. The MMPs that were originally released to clean up the damage caused by the cavity-causing bacteria are not deactivated and continue causing damage, resulting in the progression of the cavity through dentin.

So how does one have a sunny-day picnic instead of a rainy-day picnic in their body? How does one figuratively put the picnic nets over their food and enjoy the day, the equivalent of MMPs being deactivated after clearing damage from cavity-causing bacteria? And how does one make sure they do not end up swatting at bees, knocking over the dessert and getting stung – the equivalent of MMPs not being deactivated and continual destruction of dentin resulting in a progressing cavity?

A balance between MMPs and TIMPs (or MMP inhibitors) is essential for teeth to function properly (and the rest of the body). When one or the other is out of balance, cavities will develop and progress.

Excessive MMPs = Cavity progresses

Insufficient TIMPs or MMP Inhibitors

= Cavity progresses

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  1. Tod Cezil
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