Phase 2 enzyme inducers appear to stop harmful inflammation

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Phytochemicals may protect cartilage, prevent pain in joints

Phase 2 enzyme inducers appear to stop harmful inflammation

Konstantinos Konstantopoulos, s Hopkins associate professor of

chemical and biomolecular engineering, supervised doctoral student

Zachary Healy in experiments that may lead to new arthritis

treatments. Photo by Will Kirk

s Hopkins researchers have discovered that plant-derived compounds

known for their ability to protect tissue also appear to block the

activity of an enzyme that triggers inflammation in joints. Their

findings, based on experiments with human cells in a lab, could lead

to new arthritis treatments and better methods of making artificial

cartilage.

The discovery was detailed in a paper published in the Sept. 27

edition of Proceedings of the National Academy of Sciences.

The findings came to light while the researchers were studying the

wildly different ways in which cells in human blood vessels and joints

respond to pressure gradients generated from liquid moving along their

surface, a force called shear stress. In cells that line blood

vessels, the reaction to shear stress is beneficial: the boosting of

phase 2 enzymes that may protect the cells from cancer-causing

chemicals and other toxic agents. Yet in joints, the response to high

shear stress is potentially harmful: an increase in the levels of

COX-2 enzyme, which triggers inflammation and pain, and suppresses the

activity of phase 2 enzymes, ultimately causing the death of

chondrocytic cells. Healthy chondrocytes are responsible for the

smooth functioning of joints. When chondrocytes stop functioning

properly, the result can be arthritis.

The divergent responses to shear stress prompted a series of

experiments in a s Hopkins lab supervised by Konstantinos

Konstantopoulos, associate professor of chemical and biomolecular

engineering and Agarwal-Masson Faculty Scholar. His team knew that

strenuous exercise or heavy exertion of muscles can cause joints to

increase the levels of harmful COX-2 enzyme. What would happen, the

researchers wondered, if the vulnerable chondrocyte cells in human

joints were first exposed to the beneficial phase 2 enzymes?

To find out, the researchers obtained compounds that boost the

activity of helpful phase 2 enzymes. They added these phase 2 inducers

to a dish containing the chondrocyte cells that are crucial to

maintaining healthy joints. After 24 hours, the cells were subjected

to a stress test designed to mimic aspects of strenuous exercise on a

joint as well as the hydrodynamic environment in a bioreactor designed

to generate artificial cartilage.

The results were surprising. " The beneficial phase 2 enzymes somehow

seemed to prevent the activation of the inflammatory COX-2 enzyme, "

said Zachary R. Healy, a doctoral student in Konstantopoulos' lab and

lead author of the journal paper. " The phase 2 enzymes inhibited the

inflammation and the apoptosis -- the cellular suicide we'd observed. "

Some prescription drugs like Vioxx keep COX-2 enzyme at bay by

temporarily blocking its ability to send the biochemical signals that

set off pain and inflammation. When the medication is stopped,

however, the stockpiled COX-2 enzyme can resume its damaging ways.

Unlike these traditional pain killers, Healy said, the phase 2 enzyme

inducers seemed to stop the increasing activity of COX-2 enzyme.

" That means these compounds could be useful as a preventive measure,

perhaps before strenuous exercise, " Healy said. " This has the

potential for stopping pain and inflammation before they start. "

Although these experiments appeared to be the first to determine how

phase 2 enzyme inducers affect chondrocytes, these compounds have been

studied extensively by researchers at the s Hopkins School of

Medicine. Talalay, the medical school's Abel

Distinguished Service Professor of Pharmacology, has shown that phase

2 enzymes can detoxify certain cancer-causing agents and damaging free

radicals in tissue, including cells that line blood vessels. He has

isolated compounds in edible plants that boost production of phase 2

enzymes. These phytochemicals can be found in cruciferous plants,

including broccoli.

Talalay provided one of the phase 2 inducers used in Healy's

experiments. " This was the first work done in applying these

phytochemicals to chondrocytes, which are constantly under the

influence of forces because of the way we move our joints, " Talalay

said. " The phase 2 inducers seemed to counteract the effects of that

stress by inhibiting the expression of COX-2 enzyme. It's interesting

to think that people may be able to obtain this benefit through

dietary components. "

By showing a way to ward off inflammation and by providing insights

into the effects of shear stress, the new chondrocyte research may

also aid tissue engineers who are trying to grow artificial cartilage

or seeking to revitalize human cartilage in the lab. This is important

because human bodies cannot make new cartilage to replace tissue

that's lost to injury or disease.

" More research is needed, " said Konstantopoulos, who directed and

supervised the experiments. " But these discoveries could provide

guidelines for designing an ideal hydrodynamic environment in

bioreactors for generating functional cartilage as well as for the

treatment of osteoarthritis. "