UW biochemist solves riddle of collagen stability

Some scientists have posited that if the body were stripped of everything except collagen, it would maintain essentially the same form.

A UW–Madison research team has overturned a central theory about the stability of collagen, a protein that acts like a “solder” to give the body its structure and shape.

A new explanation of the phenomenon, published April 16 in the journal Nature, could expand the potential of collagen in treating serious disease, healing wounds and repairing damaged organs, said UW–Madison biochemist Ron Raines. It also holds promise in finding new treatments for arthritis, the most serious collagen-related disorder.

“We have essentially shown the way to create a stronger collagen that would not be as susceptible to breakdown in the body,” Raines said. “This research marks a fundamental change in how we understand the structure and stability of collagen.”

Collagen is an abundant protein found in skin, bone, cartilage and tendons. It forms strong fibers and serves as a connective tissue between cells. If scientists can develop a more stable collagen for human use, far more important medical therapies would be possible, Raines said. Collagen breakdown is at the heart of many serious diseases, such as arthritis, rheumatism, brittle bones, lupus, cirrhosis and cataracts. Providing a stronger source of collagen could also lead to development of a natural “solder” that heals wounds without scars, or can strengthen frail bones.

Most people have heard of collagen in the realm of cosmetic surgery, where a purified form of bovine collagen is used to provide fuller lips or smooth away wrinkles. But those improvements don’t last, Raines said, because the material starts breaking down after a few months.

Collagen loses its stability over time by actually unraveling at the molecular level, which makes it susceptible to enzymes that cause it to degrade. The aging process or genetic abnormalities can cause this unraveling to occur, Raines said.

Collagen is created by cells with a complex and repeated chain of amino acids, with different helices performing specialized tasks in the body. There are ten distinct types of collagen in the human body, Raines said.

About 25 years ago, biochemist Darwin Prockop unlocked some of the first clues to the molecular stability of collagen. He found that the hydroxyl (or water-like) groups found in collagen greatly increased the stability of the collagen triple helix. The prevailing explanation has been that “bridging water molecules” helps hold the triple helix together.

In 1994, scientists showed for the first time that those water bridges are present in collagen. But Raines’ research team was skeptical of that explanation, since it would require seemingly too much order. Raines said the body would have to immobilize about 500 water molecules for every triple helix of collagen.

Using synthetic chemistry, Raines’ lab replaced the hydroxyl groups in collagen with fluorine, an atom that cannot form hydrogen bonds. The result was a dramatic increase in collagen stability.

Raines said the new explanation is based on an inductive effect – that the molecules are organizing themselves through electrostatic forces. The fluorine atoms are soaking up electrons, which organizes the collagen chains into a highly stable triple helix.

The stability of collagen is measured by its “melting point,” or the temperature at which the strands begin to unravel, Raines said. In Prockop’s experiment, he produced collagen that was stable at up to 58 degrees Celsius. But the fluorine-laced collagen in Raines’ lab remained stable at up to 91 degrees, or 196 degrees Fahrenheit.

“This would make collagen of much greater value in biotechnology, because it would not degrade at temperatures so close to those of the human body,” Raines said.

Raines’ research, funded by the National Institutes of Health, will now turn to whether natural collagen can also be strengthened. Natural collagen cannot be treated with fluorine, but there likely are ways to make natural collagen achieve similar stability.

His work is also being supported by The Arthritis Foundation. Although prospects are well in the future, medical researchers are studying whether collagen replacement therapy could alleviate some of the damage caused by arthritis.

“In arthritis sufferers, the body’s immune system is tricked into thinking its own collagen is a foreign entity that must be destroyed,” Raines said. “That process might be triggered when collagen begins to unfold.”

Collagen therapy could work much like bone or skin grafting, where new material replaces the lost or damaged tissue, he said. Some early, experimental studies are also looking at collagen as a raw material for heart valve or vessel repair, in reconstructing damaged cartilage or ligaments, and for corneal grafts.

Its sheer abundance in the body makes it an exciting and important area for medicine, Raines said. Some scientists have posited that if the body were stripped of everything except collagen, it would maintain essentially the same form.