Sore knee? Tennis elbow? The common prescription is simple: Take a couple of aspirin, or the equivalent, and don't call the HMO in the morning. Anti-inflammatory drugs douse the symptoms of minor joint pain pretty well. What isn't exactly clear is how.
Wendy Krause, a graduate student in polymer science at Penn State, thinks it's a matter of osmosis. But then Krause and her adviser, associate professor of polymer science Ralph Colby, are looking at joint swelling—inflammation—from a perspective different than most. They study fluid dynamics.
Polymers are long-chain molecules, many of which have interesting mechanical properties, particularly in solution, Krause explains. "My research before this has all been on synthetic polymers," she continues, "but I'm interested in moving over to a medical-related field, so I wanted to look at some natural ones." That inclination, and the fact that "Dr. Colby has been having some joint problems," Krause says, led to an investigation of the properties of hyaluronic acid.
Hyaluronic acid, Krause explains, is a polyelectrolyte—a charged polymer—that has diverse functions in the human body. Its viscous nature, for instance, gives shape to the eyeball. "If you ever dissected a cow's eyeball in elementary school," she says, "hyaluronic acid in solution is the stuff you squeezed out of the back—it's like runny jello." It is also a key component in the fluid that bathes and lubricates the knees, elbows, and wrists.
This fluid is a solution of blood plasma filtered through the semipermeable membrane that surrounds the joint. This membrane allows smaller molecules—water, salts, amino acids—to pass through, while keeping the larger polyelectrolytes inside where they're needed.
Here's where osmosis comes in. "If you have a solution divided by a semipermeable membrane," Krause explains, "the chemical potentials have to be equal on both sides. You will have molecules flowing from one side to the other until you reach this equilibrium." When the necessary balance is reached, so-called osmotic pressure causes the movement to cease.
Joint swelling, it turns out, is accompanied by an increase in osmotic pressure. For Krause and Colby, that observation rang a bell; to understand why requires knowing a little more about how polyelectrolytes are put together.
"A polyelectroyte has a polymer backbone," Krause explains, "and fixed to this are negatively charged acid groups." Because a molecule has to maintain a neutral charge, for each of these acid groups there has to be a positively charged group along for the ride. In this case, these are mostly sodium ions. In solution, however, poly-electrolytes like to bind with proteins, which can be positively charged, and when they do this something interesting happens. The sodium ions, no longer needed for neutrality, are released. The result is an increase in osmotic pressure.
Could this be what happens in sore joints? To find out, Krause and Colby searched the literature and found the osmotic pressure data for a solution of hyaluronic acid, that of a solution of serum albumin—one of the most plentiful proteins in joint fluid (and, Krause says, "a scavenger that likes to bind")—and that of a solution of the two combined. The osmotic pressure of the latter solution was higher than the pressures of the first two solutions added together. They concluded that the hyaluronic acid and serum albumin were indeed hooking up—and that their interaction was crucial to inflammation.
"We think the hyaluronic acid-albumin complex is always present," Krause says. Inflammation results when that interaction is enhanced—by the presence of extra albumin, say. Albumin can cross the joint's semipermeable membrane, Krause notes. Rheumatoid arthritis sufferers, it has recently been shown, have a higher-than-nor mal concentration of albumin in their joint fluid, and a lower-than-normal concentration in their plasma.
All of which brings things round to aspirin. If the hyaluronic acid-albumin complex is what leads to inflammation, Krause and Colby reckon, maybe aspirin does its work by disrupting this interaction. "We suspect that aspirin restricts the formation of the complex by binding to either hyaluronic acid or to albumin itself," Krause says. "We're testing this idea now, by measuring viscosities." The viscosity of a fluid, she explains, is related to the sizes of the molecules it contains. A solution containing hyaluronic acid mixed with albumin should have a higher viscosity than one containing hyaluronic acid alone. And if aspirin does in fact disrupt the complex, then the viscosity of a solution containing hyaluronic acid, albumin, and aspirin should drop off. In early tests, "we've seen the latter, but not the former," Krause reports. "So it looks like it's more complicated than we suspected.
"We need to understand the complex itself better before we really look at how drugs interact with it," she stresses. "But if we can do that—and if we can give drug designers a new insight into how aspirin works—they might be able to tailor something that works even better."
Wendy E. Krause is a Ph.D. student in chemistry in the Eberly College of Science, 152 Davey Lab, University Park, PA 16802; 814-865-1213; wek4@psu.edu. Her adviser, Ralph H. Colby, Ph.D., is associate professor of polymer science, College of Earth and Mineral Sciences, 309 Steidle Bldg.; 863-3457; rhc@plmsc. psu.edu. This work was supported in part by the National Science Foundation.