For more than 15 years, Alan Grodzinsky and his students have probed the mysteries of cartilage-the tissue that serves as a cushion between abutting bones-with the ultimate goal of understanding cartilage diseases such as osteoarthritis on a molecular level.
The work could help lead to cures for these diseases as well as techniques for repairing cartilage damaged in accidents.
Now the professor in electrical engineering and computer science will be able to continue those studies for another 10 years, thanks to an award he recently received from the National Institutes of Health.
The MERIT (Method to Extend Research in Time) Award "acknowledges consistent and excellent contributions to scientific knowledge" and is "designed to provide a few outstanding investigators with the opportunity for long-term stable support," according to the NIH. The award could amount to more than $2 million distributed over the 10-year period.
Professor Grodzinsky's work focuses on how biological and physical forces interact to build or degrade cartilage. A better understanding of this system could bring a cure for osteoarthritis, a disease in which the tissue is slowly destroyed. Currently the only "treatment" for late-stage disease is to replace the affected joint with an artificial one. (In the US, an estimated one million joint replacements will be performed annually over the next several years, according to Dr. Henry Mankin of Massachusetts General Hospital.)
The work could also lead to techniques for repairing cartilage damaged in accidents (hundreds of thousands of Americans are injured in this way every year). Damaged cartilage cannot heal on its own and can lead to osteoarthritis.
Cartilage is composed of a stiff, spongy matrix and the cells that produce that matrix (the cells make up less than 10 percent of the overall tissue). Scientists know that cartilage production and degradation is regulated in part by the physical forces or loads put on it as we stand or walk, for example. "Normal" loads actually stimulate cartilage cells to make more matrix, yet excessive loads or immobilization of a joint can do the opposite. Why? And under what conditions does the matrix begin to break down?
To answer these and related questions, Professor Grodzinsky and colleagues devised a system to study disks of living bovine cartilage outside of the body, or in vitro. The system is important because cartilage is difficult to study inside the body (in vivo). "With in vivo studies it's hard to accurately measure [the forces] that particular regions of cartilage are subjected to," said Professor Grodzinsky, who heads the Continuum Electromechanics Group in the Laboratory for Electromagnetic and Electronic Systems.
With the MIT system, however, "we can apply and simulate well-defined sets of strains and stresses that cartilage is subjected to in a joint, then we can use techniques developed by biochemists and molecular biologists to measure cellular response, such as the rate at which [cartilage] cells make more matrix," Professor Grodzinsky said.
The NIH cited the system as one example of "the impressive progress" the Grodzinsky team has made over previous funding periods, and went on to describe other important studies the team has conducted.
For example, using their in vitro system the team showed that "static [or steady] compression of cartilage can inhibit matrix production, while cyclic compressions-typical of moderate exercise-stimulate matrix production," Professor Grodzinsky said. The team also identified the "ranges of mechanical forces and frequencies that produced these results."
Further, in collaboration with biochemists at the Shriners Hospital in Tampa, FL, the team explored the effects of these forces on the production of specific matrix molecules, such as proteoglycans, collagens, and other proteins, and "found that mechanical forces had very different effects on different [matrix] molecules," Professor Grodzinsky said. "This suggests that there are very specific biosynthetic pathways connected to mechanical forces."
The group plans to further define the effects of mechanical loads on synthesis and degradation of specific matrix molecules. Such studies "will allow us to probe disease-related mechanisms and the effects of compression on cartilage repair," Professor Grodzinsky said.
Another research result involves the molecular structure of one kind of matrix molecule, the proteoglycan, and its relationship to overall cartilage function. Professor Grodzinsky explained that to electrical engineers in particular, proteoglycan is very interesting because it contains many electrically charged groups. "It's like a tree with many branches and needles," he said, "and each needle might have 50 to 100 of these charged groups along it." The "needles" repel each other as well as needles on adjacent proteoglycan molecules.
The Grodzinsky team showed that this repulsion is responsible for at least 50 percent of the stiffness or rigidity typical of cartilage when it is compressed. Furthermore, the researchers showed a connection between the molecular-level structure of this complex molecule and cartilage's macroscopic mechanical properties. "This is an excellent example of the progress this investigative team has made," the NIH said.
Professor Grodzinsky emphasized the interdisciplinary nature of the work. Members of his team, which include principal research engineer Dr. Eliot Frank, two other staff members, eight graduate students and one postdoc, come from the Departments of Electrical Engineering and Computer Science, Mechanical Engineering, Materials Science and Engineering, Chemical Engineering, and the Harvard-MIT Division of Health Sciences and Technology (HST). (Professor Grodzinsky also has joint appointments in mechanical engineering and HST.)
In addition, he noted the "critically important" impact students have had on this work. "Much of the work cited by NIH has come from graduate and undergraduate thesis research," he said. The students participate in extensive collaborations with orthopedic surgeons and scientists at Massachusetts General Hospital, Brigham and Women's Hospital and abroad.
The MERIT award will permit the Grodzinsky team to continue its work on the mysteries of cartilage and tackle new avenues. Concluded the NIH: "The prospects are high for important, basic discoveries."
A version of this article appeared in the November 9, 1994 issue of MIT Tech Talk (Volume 39, Number 11).
