The discovery was detailed in a paper published in the Sept. 27 edition of Proceedings of the National Academy of Sciences.
Thefindings came to light while the researchers were studying the wildlydifferent ways in which cells in human blood vessels and joints respondto pressure gradients generated from liquid moving along their surface,a force called shear stress. In cells that line blood vessels, thereaction to shear stress is beneficial: the boosting of phase 2 enzymesthat may protect the cells from cancer-causing chemicals and othertoxic agents. Yet in joints, the response to high shear stress ispotentially harmful: an increase in the levels of COX-2 enzyme, whichtriggers inflammation and pain, and suppresses the activity of phase 2enzymes, ultimately causing the death of chondrocytic cells. Healthychondrocytes are responsible for the smooth functioning of joints. Whenchondrocytes stop functioning properly, the result can be arthritis.
Thedivergent responses to shear stress prompted a series of experiments ina Johns Hopkins lab supervised by Konstantinos Konstantopoulos,associate professor of chemical and biomolecular engineering andAgarwal-Masson Faculty Scholar. His team knew that strenuous exerciseor heavy exertion of muscles can cause joints to increase the levels ofharmful COX-2 enzyme. What would happen, the researchers wondered, ifthe vulnerable chondrocyte cells in human joints were first exposed tothe beneficial phase 2 enzymes?
To find out, the researchersobtained compounds that boost the activity of helpful phase 2 enzymes.They added these phase 2 inducers to a dish containing the chondrocytecells that are crucial to maintaining healthy joints. After 24 hours,the cells were subjected to a stress test designed to mimic aspects ofstrenuous exercise on a joint as well as the hydrodynamic environmentin a bioreactor designed to generate artificial cartilage.
Theresults were surprising. "The beneficial phase 2 enzymes somehow seemedto prevent the activation of the inflammatory COX-2 enzyme," saidZachary R. Healy, a doctoral student in Konstantopoulos' lab and leadauthor of the journal paper. "The phase 2 enzymes inhibited theinflammation and the apoptosis -- the cellular suicide we'd observed."
Someprescription drugs like Vioxx keep COX-2 enzyme at bay by temporarilyblocking its ability to send the biochemical signals that set off painand inflammation. When the medication is stopped, however, thestockpiled COX-2 enzyme can resume its damaging ways. Unlike thesetraditional pain killers, Healy said, the phase 2 enzyme inducersseemed to stop the increasing activity of COX-2 enzyme.
"Thatmeans these compounds could be useful as a preventive measure, perhapsbefore strenuous exercise," Healy said. "This has the potential forstopping pain and inflammation before they start."
Although theseexperiments appeared to be the first to determine how phase 2 enzymeinducers affect chondrocytes, these compounds have been studiedextensively by researchers at the Johns Hopkins School of Medicine.Paul Talalay, the medical school's John Jacob Abel DistinguishedService Professor of Pharmacology, has shown that phase 2 enzymes candetoxify certain cancer-causing agents and damaging free radicals intissue, including cells that line blood vessels. He has isolatedcompounds in edible plants that boost production of phase 2 enzymes.These phytochemicals can be found in cruciferous plants, includingbroccoli.
Talalay provided one of the phase 2 inducers used inHealy's experiments. "This was the first work done in applying thesephytochemicals to chondrocytes, which are constantly under theinfluence of forces because of the way we move our joints," Talalaysaid. "The phase 2 inducers seemed to counteract the effects of thatstress by inhibiting the expression of COX-2 enzyme. It's interestingto think that people may be able to obtain this benefit through dietarycomponents."
By showing a way to ward off inflammation and byproviding insights into the effects of shear stress, the newchondrocyte research may also aid tissue engineers who are trying togrow artificial cartilage or seeking to revitalize human cartilage inthe lab. This is important because human bodies cannot make newcartilage to replace tissue that's lost to injury or disease.
"Moreresearch is needed," said Konstantopoulos, who directed and supervisedthe experiments. "But these discoveries could provide guidelines fordesigning an ideal hydrodynamic environment in bioreactors forgenerating functional cartilage as well as for the treatment ofosteoarthritis."
Funding for the research was providedby a DuPont Young Professor Award, a National Science FoundationGraduate Research Fellowship and an Achievement Reward for CollegeStudents Fellowship. Healy's co-authors on the PNAS paper were Talalay,Konstantopoulos, Norman H. Lee of the Institute for Genomic Research,Xiangqun Gao of the Department of Pharmacology and Molecular Sciencesat the Johns Hopkins School of Medicine, Mary B. Goldring of theHarvard Institutes of Medicine, and Thomas W. Kensler of the Departmentof Environmental Health Sciences in the Johns Hopkins Bloomberg Schoolof Public Health.
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