Researchers discover how rheumatoid arthritis causes bone loss.

Researchers have discovered key details of how rheumatoid arthritis (RA) destroys bone, according to a study published in the Aug. 22 edition of the Journal of Biological Chemistry. The findings are already guiding attempts to design new drugs to reverse RA-related bone loss and may also address more common forms of osteoporosis with a few adjustments (see also University of Rochester Medical Center).

Two million Americans suffer from rheumatoid arthritis (RA), which causes swelling, pain and deformity in joints and also lead to the thinning of bone. In autoimmune diseases like RA, the body's disease-fighting immune cells mistakenly identify parts of a person's body as foreign invaders, akin to bacteria, and produce chemicals to destroy them. Among the immune chemicals known to play a central in autoimmune disease is tumor necrosis factor alpha (TNF alpha), which ramps up the production of immune cells and chemicals as part of the body's response to disease. When overproduced in RA patients, TNF alpha signals for the destruction of cartilage and bone.

Beyond its control over immune cells, TNF alpha also influences bone mass. Human bone is continually regenerated to maintain strength. Under the control of signaling molecules which include TNF alpha, two cell types, balanced against each other, make bone recycling possible. Osteoclasts break down aging bone to make way for new bone, while osteoblasts build new bone at the sites where osteoclasts have removed it. Going into the study, the field understood that TNF alpha decreases the number of bone-building osteoblasts, but not how. The current study provides the first direct proof that the TNF alpha affects osteoblasts through an enzyme called Smad Ubiquitin Regulatory Factor 1 (Smurf1), which in turn shuts down two proteins that would otherwise drive bone-building.

While traditional RA drugs like NSAIDs and steroids treat symptoms, a newer class of best-selling drugs (e.g. Humira, Remicade and Enbrel) reverses the disease process by shutting down TNF alpha activity. While the new drugs are effective for many patients, others experience infections and even lymphoma in a few cases. The new drugs are based on bioengineered versions of proteins made by human immune cells called antibodies, and are very expensive to make. Thus, the field has been searching for smaller, simpler chemicals that would be effective, but with lower costs and fewer side effects.

"The significance of our study is that it identifies SMURF1 as the signaling partner through which TNF does damage in RA-related bone loss," said Lianping Xing, Ph.D., assistant professor of Pathology and Laboratory Medicine at the University of Rochester Medical Center. "That has enabled researchers to begin designing small molecule drugs to shut down the action of Smurf 1 and its relatives. Furthermore, since mice engineered to have less Smurf1 expression develop thicker bones, future drugs that shut down Smurf1 may be also useful against more common forms of osteoporosis simply by changing the dose. Of course, this is early-stage work with many obstacles ahead, but it is exciting nonetheless."

Study Details

In the late 1990s, Gerald H. Thomsen, Ph.D., at Stony Brook University in New York discovered that Smurf1 helps to attach a protein tag called ubiquitin to aging proteins in need of disposal. The tag then ...