Invasion. RASFs (black arrows, left) degrade healthy cartilage in mice (white arrows). This once-healthy piece of cartilage was ravaged by RASFs migrating through the body (right).

Stephanie Lefevre and Elena Neumann

Arthritis on the Move

The same cells that ravage the cartilage of rheumatoid arthritis patients also carry the disease from joint to joint, a new study suggests. The work points to several possibilities for halting the spread of this crippling condition.

Rheumatoid arthritis typically appears in a single joint at first, but it often spreads throughout much of the body within a few years. The autoimmune disease destroys cartilage padding between bones and causes inflammation in joints, resulting in intense pain and lack of mobility. It differs from osteoarthritis, which is the normal, long-term wearing away of the padding in isolated joints.

Scientists had known that certain types of fibroblasts--cells that help bind wounds and build the connective tissue that supports other cells--are responsible for damaging cartilage, says Elena Neumann, a molecular biologist at Justus-Liebig University in Bad Nauheim, Germany. These rheumatoid arthritis synovial fibroblasts (RASFs) appear in the fluid within joints and secrete enzymes that decompose cartilage.

To figure out whether RASFs could spread arthritis from joint to joint, Neumann and her colleagues implanted human cartilage under the skin of mice genetically engineered not to reject tissue from a different species. On one flank, the mice received healthy, normal cartilage; on the other, they received cartilage abundant with human RASFs.

After 60 days, the RASFs had invaded and damaged the healthy cartilage in most mice, the team reports online this week in Nature Medicine. Control mice that received healthy cartilage in both flanks showed little damage, as did mice that received implants of fibroblasts from patients with osteoarthritis, which does not spread from joint to joint.

To show that RASFs had traveled within the body (and weren't just, say, turned on remotely by another secretion), the scientists dissected the organs of 20 of the mice. They found little trace of RASFs in most internal organs, but they did find a high concentration in the spleen. That's an important clue, Neumann says, because the spleen filters blood cells from the bloodstream. When the team examined 40 other mice with RASF/cartilage implants, it found human RASFs in the blood of about half, strongly suggesting that the RASFs use the bloodstream to invade the rest of the body.

How do the RASFs make it into the bloodstream in the first place? Much like metastasizing tumor cells, the team found, the fibroblasts can wriggle through the cells that line and protect blood vessels.

Neumann's team did not find RASFs in the joints of the mice, as is seen in arthritis patients. Neumann suspects that RASFs can invade cartilage only if it already has small nicks or other tiny openings that result from wear and tear. This probably explains why it takes years for rheumatoid arthritis to spread in humans.

Scientists could potentially develop a treatment for arthritis by preventing RASFs from invading the bloodstream, traveling around in the blood, or jumping from blood to healthy tissue, Neumann says. Such treatments might not prevent rheumatoid arthritis from appearing in a patient, she says, but they would halt its spread to other joints.

It's a "very important" and "very thorough" paper, says James Woods, a microbiologist at Midwestern University in Downers Grove,, Illinois, who has studied the migration of RASFs: "The fibroblasts that were active, they are usually thought of as a resident [i.e., nonmobile] cell. This paper is shifting that mentality." Developing a cure, he says, "definitely will be a challenge, but knowing the right target cell to go after is a critical first step." In the future, he says, the ability of RASFs to invade cartilage could even be turned to medicine's advantage by reprogramming them, perhaps with gene therapy, to deliver proteins that heal the joint instead of demolishing it.