Antibody may explain collagen’s undoing

Potential culprit in rheumatoid arthritis identified

A lone antibody can unravel collagen fibers, possibly contributing to the destruction of cartilage in people with rheumatoid arthritis.

TOGETHER, APART Collagen forms ordered bundles (left), but a newly identified antibody strips away a protein called biglycan, which helps hold the collagen bundles together, causing the bundles to fall apart (right). O. Antipova and J.P.R.O. Orgel/PLoS ONE 2012

Picking apart proteins was thought to be a job reserved for enzymes and immune cells. But an antibody that attacks a protein called biglycan can cause bundles of collagen fibers to fray like the ends of a string of yarn, Joseph Orgel and Olga Antipova of the Illinois Institute of Technology in Chicago report online March 13 in PLoS ONE. And the antibody works alone, with no help from destructive cells or enzymes, the researchers found.

Rheumatoid arthritis is a disease in which the immune system attacks and destroys the cartilage — which is composed mainly of collagen — that cushions joints.  Previous research has shown that patients with the disease have high levels of the biglycan-attacking antibody in the fluid that lubricates joints. Antibodies are known to guide immune cells to destroy invading microbes or dangerous proteins, but not — until now — to do demolition work on their own.

“This discovery was hiding in plain sight for a long time,” says Orgel. He and Antipova uncovered the antibody’s ability thanks to “a harebrained scientific idea” Orgel conceived, he says. The idea was to use antibodies that target proteins associated with collagen in X-ray–based experiments designed to reveal where those proteins interact with collagen fibers.

In preparation for those experiments, Antipova isolated collagen fibers from eel-like fish called lampreys and microscopically studied the sites where the biglycan antibody attached along the collagen fiber. Without the antibody, the collagen fibers were arranged in orderly packages, resembling bundles of long tubes. But adding the antibody caused the bundles to fray.

The researchers determined that biglycan must be wrapped around groups of collagen fibers like a ribbon around a bundle of sticks. The antibody latches onto biglycan and physically pulls it away from the collagen fibers, the researchers surmise. “It’s like untying a shoelace — just that one tug and it falls apart,” Orgel says.

Other researchers are not convinced, though, that the antibody helps explain rheumatoid arthritis in humans. In the body, cartilage is coated with a layer of protective proteins, says Mary Goldring, a cartilage biologist at Weill Cornell Medical College in New York City. “I think it’s real and interesting from a biophysical point of view,” she says of the antibody idea, “but I just don’t think it’s a targetable and important part of cartilage breakdown in rheumatoid arthritis.”

Enzymes and immune cells would have to chew through the protective layers before the antibody could ever get at the collagen inside. Even if the antibody does contribute to cartilage breakdown, cells and enzymes are still likely to be the major destructive forces in rheumatoid arthritis, Goldring says.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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