Tooth decay may result from immune response, not just bacterial plaque

U of T researchers find evidence for maverick theory first published in 1970

Tooth decay may result from immune response, not just bacterial plaque

Cavities in teeth may result from an immune system response, not just bacteria, according to a recent U of T study. This counters decades of established thinking in dental research.

In 1970, Dr. John Gabrovsek of the Cleveland Clinic published research in the Journal of Dental Research that found that our immune system may contribute to dental cavities. But during the almost 50 years since it was published, most dental researchers have not taken Gabrovsek’s theory seriously — until U of T’s findings were published in April.

The research was spearheaded by Dr. Yoav Finer and Dr. Michael Glogauer, both professors at the U of T Faculty of Dentistry.

“Glogauer approached me a few years ago, [and] told me that these immune system cells have the same enzymes and more enzymes than bacteria have, so why not check them?” Finer explained to The Varsity.

The research team began by examining immune cells called neutrophils. Neutrophils are a type of white blood cell routinely found in the mouth, and they act as the first line of defense against harmful bacteria.

However, as these immune cells fight against harmful pathogens that can damage teeth, they can also cause collateral damage to what they are originally trying to protect — our teeth.

While bacteria still cause most of the damage that results in tooth decay, Finer explained that the research team has found evidence that these immune cells also contribute to cavity formation.

How the research team arrived at the discovery

Through years of study, the team created samples from extracted teeth and then used acid to remove minerals from them.

The application of acid mimicked the effect that harmful bacteria have on teeth, as the acid they release causes tooth decay.

The researchers then isolated neutrophils from human volunteers and kept them at a warm temperature with the extracted teeth.

“That was a daily procedure because you can’t culture these cells — neutrophils — unlike bacteria,” said Finer. “You need to get these cells isolated from the blood donors on a daily basis or every other day.”

The team found that while these immune cells help protect teeth from damage caused by bacteria, they can also remove minerals from tooth dentin, as well as break down white-coloured tooth fillings.

A possible explanation for why neutrophils can degrade teeth, according to Finer, is their enzymes — biological molecules that speed up chemical reactions. However, it remains unclear which type of enzyme could be responsible for contributing to dental decay.

Applications of the research findings

Protecting our teeth is important, as dental diseases can affect not just our mouths, but our overall health. For example, bacteria that cause gum disease can lead to infections of our lungs and increased risk of blockage in arteries that can damage our hearts.

Glogauer’s research team has been developing a mouth rinse that could prevent some of the degradation caused by these immune cells to apply the findings to clinical dentistry.

Finer’s research team has also been developing a dental varnish that contains anti-degradative factors to help counteract the effect of both bacteria and neutrophils on teeth.

However, preventing tooth decay ultimately comes down to maintaining good oral hygiene.

“With a recommended toothpaste and toothbrush, keeping good oral hygiene is the key,” explained Finer. “It’s our first line of defense and can eliminate a lot of problems… the immediate thing is making sure you keep your sugar consumption under control.”

A loophole in the cancer cell cycle is found

Researchers uncover an inhibitor that could halt cancer progression

A loophole in the cancer cell cycle is found

YAP and TAZ are proteins that have long been recognized for their role in regulating transcription — a process in which the information in DNA is copied into RNA — and are particularly relevant in cancer development.

A recent study in Nature Communications led by Mandeep K. Gill in U of T’s Department of Biochemistry identified NUAK2 as a gene that could control YAP/TAZ activity.

In normally functioning cells, YAP and TAZ are responsible for forming and regenerating tissues. In tumours, however, these proteins are able to initiate and metastasize, or spread, cancer cells to other parts of the body, as well as initiate the tumours.

“The relatively recent discovery (roughly 10 years) of the so called  ‘Hippo pathway’ which normally acts to limit excess cell growth and the demonstration that it is turned off in most cancers has provided a new target for the development of therapeutics,” explained Liliana Attisano, a principal investigator of the study also from the Department of Biochemistry, in an email to The Varsity.

The Hippo pathway is a process that controls tissue and organ development in mammals, especially in their size, by regulating cell growth and death, and controls the transcriptional activity of YAP and TAZ proteins.

The pathway can be activated by various factors, after which it engages its core cassette — a subunit made of enzymes known as kinases, which are involved in the movement of phosphate groups, or phosphorylation.

When a cascade of phosphorylation — the addition of a phosphate group — occurs in the cassette, YAP and TAZ are marked with phosphate groups and are targeted for degradation.

When the Hippo pathway is inactive, however, YAP and TAZ accumulate in the nucleus and latch on to the DNA-binding proteins in there, which can lead to cancer cell proliferation. 

Attisano and her team discovered NUAK2 was found to encode a protein that results in even more YAP and TAZ getting into the cell’s nucleus to further promote abnormal cell growth.

The researchers started by conducting studies in breast cancer cells and were able to identify  the kinase NUAK2 as a positive regulator of YAP and TAZ activity.

According to the study, “NUAK2 functions in a kinase-dependent manner to promote nuclear YAP/TAZ localization and activity” and promotes YAP and TAZ activity in a positive feedback loop.

A decrease in NUAK2 is therefore found to reduce transcriptional activity and the quantity of YAP and TAZ in the nucleus. As well, kinase-deficient NUAK2 was found to restore YAP and TAZ localization in the nucleus, which deemed NUAK2 an activator of YAP and TAZ activity.

“We found a way to restore the activity of the pathway (by removing or blocking NUAK2 activity),” wrote Attisano.

A lack of NAUK2 in cells showed a reduced cell growth and robust tumour growth in mice.

Tests were conducted on bladder cancer cells to determine the implications for human tumour progression. Larger increases of NUAK2 were found in high-grade samples that came from patients who had experienced a relapse.

These findings could be applied to cancer treatments as blocking the expression of or inhibiting NUAK2, YAP, and TAZ appears to restore Hippo pathway activity and cell growth, thus limiting tumour progression.

“There is still a long road ahead,” wrote Attisano. “But the next step would be [to] develop specific and potent compounds that can be tested in mouse and human organoid models with the long-term goal of… identifying a drug that can be used in patients.”