One-Two Molecular Punch At Root of Common Arthritis

Scientists have discovered in unprecedented detail the molecular forces that conspire to damage bone in patients with psoriatic arthritis, a disease that affects an estimated 500,000 to 1 million people in the United States. New findings show that people with the disease are awash in a type of cell that specializes in dissolving bone, and their joints have high amounts of a protein that persuades those cells to settle into joints, where most damage is done. Discovery of the one-two punch helps doctors understand why patients are responding so well to new medicines, and it opens the door to new remedies — all for a disease that had no approved treatment little more than a year ago.

The work by scientists at the University of Rochester Medical Center appears in the March 15 issue of the Journal of Clinical Investigation.

The findings come at a time of tremendous change in the treatment of the disease, which is less known but can be just as crippling as rheumatoid arthritis. The autoimmune condition mostly affects people who have psoriasis — doctors estimate that 10 to 15 percent of people who have psoriasis also develop psoriatic arthritis, usually in their 20s or 30s. Patients usually have a great deal of pain, swelling and inflammation as the disease literally eats away at their joints, causing some bones or digits such as fingers or toes to shrink or literally disappear while also triggering abnormal, disfiguring and disabling bone growth in their hands, feet, spine, and other joints.

The researchers studied 30 patients with the disease and 12 healthy people to understand the events that lead to bone destruction. A team led by Christopher Ritchlin, M.D., director of the Clinical Immunology Research Unit at the university’s Strong Memorial Hospital, analyzed blood samples and examined cells from the synovium, the joint lining that normally nourishes a joint but becomes invasive and destructive in patients with psoriatic arthritis. The work expands on basic research previously performed in genetically modified knockout mice.

Ritchlin’s team uncovered two key molecular steps. First, they found that compared to people without the disease, patients with psoriatic arthritis have circulating in their bloodstream 45 times as many osteoclast precursors, which eventually form osteoclasts that specialize in breaking down or eroding bone.

But an over-abundance of these cells is only part of the story. Scientists also found that patients have high amounts of a molecule known as RANKL in their joints. It’s the presence of RANKL that prompts osteoclast precursors to mature into full-fledged fledged osteoclasts, which settle onto a bone surface like little suction cups and begin pumping out acid to dissolve bone.

Such activity on a limited basis happens in healthy people every day: Osteoclasts help to remodel or remake 10 percent of our skeleton each year. Just as roadways need to be maintained every year, so do our bones — osteoclasts strip off the worn or old layer of bone, clearing the way for cells known as osteoblasts to come in and lay down fresh, healthy bone. RANKL is like a molecular flagman that tells precursor cells to mature into osteoclasts, settle onto the bone surface, and begin their work. In patients with psoriatic arthritis, the osteoclasts are running amok — there are too many of them, and they’re munching and eroding bone where they should not.

In addition to uncovering the molecular roots of the disease, Ritchlin’s team also showed that the assault on a patient’s joint comes on two fronts, from within the joint, as expected, but also from inside the bone. “We’ve found nests of osteoclasts deep within the bone, just perched and ready to attack. These are big monster cells — giant compared to other nearby cells. They appear to migrate toward the joint, where they do their damage,” says Ritchlin.

Currently the team is working on ways to use the new information to diagnose, track and possibly predict the course of the disease in patients much more quickly than possible today. This might involve a rapid blood test to predict how the disease will progress in certain patients, or to determine the effectiveness of a new medication. The research may also open up new drug strategies, such as a compound that reduces RANKL or increases a substance called osteoprotegerin (OPG), which Ritchlin’s team found counters the effects of RANKL on osteoclast precursors in psoriatic arthritis patients.

Ritchlin is excited by the results, which come on the heels of recent new treatments. Until early last year there were no medicines approved to treat the condition; last year the drug Enbrel was approved to treat the disease, and several other agents are either being tested or are available because they have been approved to treat other forms of arthritis.

“The change in these patients’ lives is dramatic,” says Ritchlin, a rheumatologist who treats hundreds of patients with psoriatic and rheumatoid arthritis, a related disorder where Ritchlin suspects some of the same molecular players are involved.

“Within days of beginning treatment most people have less pain, swelling and stiffness, and they have more energy and mobility. It’s amazing to watch — suddenly their complaints involve muscle strains and other symptoms of over-activity. It’s really the metamorphosis of a human being. It’s been very satisfying to see, especially with a disease that was neglected for so long.”

When Ritchlin started studying psoriatic arthritis nine years ago, doctors had little understanding of its causes. With funding from the National Institutes of Health (NIH), Ritchlin has become an expert on the disease — he was the first to describe the key role of tumor necrosis factor (TNF) alpha, a compound that rouses other immune cells to attack the patient’s body. Most of the new treatments are based on targeting TNF, which plays a role in creating the greater numbers of osteoclast precursor cells. The team also showed in parallel studies that mice with more TNF have more osteoclast precursor cells, and that the drugs currently used to treat the disease knock down the number of these bone-damaging osteoclasts in the bloodstream anywhere from 79 to 96 percent.

“This is a great illustration of taking advances in the laboratory and bringing them to patients’ lives,” says Ritchlin. “The work in transgenic mice matched perfectly what we were seeing in patients, and the two have come together to help us understand and hopefully improve upon a very effective therapy.”

Also leading the research effort was Edward Schwarz, Ph.D., of the Center for Musculoskeletal Research. Other members of the team included Rochester researchers Sally Haas-Smith and Ping Li, and former Rochester bone pathologist David Hicks, now at the Cleveland Clinic. In addition to the NIH, funding from the Howard Hughes Foundation helped support the work.

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