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Researchers report new findings on how rheumatoid arthritis causes bone loss
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Scientists 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.
Investigators from the University of Rochester Medical Center, N.Y., said that 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 role 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, the researchers said in a press release. 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, according to the researchers. Under the control of signaling molecules (including TNF-alpha), two cell types, when balanced against each other, make bone recycling possible.
The current study provides the first direct proof that 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, according to the press release.
While traditional RA drugs like NSAIDs and steroids treat symptoms, a newer class of best-selling drugs, including adalimumab (Humira, Abbott), infliximab (Remicade, Centocor) and etanercept (Enbrel, Amgen/Wyeth) reverses the disease process by shutting down TNF-alpha activity, according to the press release. But while the new drugs are effective for many patients, others experience infections and even lymphoma in a few cases.
"The significance of our study is that it identifies SMURF1 as the signaling partner through which TNF does damage in RA-related bone loss," co-investigator Lianping Xing, MD, PhD, said in the press release. "That has enabled researchers to begin designing small molecule drugs to shut down the action of SMURF1 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," Xing said in the press release. "Of course, this is early-stage work with many obstacles ahead, but it is exciting nonetheless."
Xing added that in inflammatory diseases like RA, the function of a group of enzymes like SMURF1 may get turned on to cause proteasome degradation of key regulator proteins, leading to bone loss. Consequently, "The real, future solution will involve a treatment that specifically addresses each of these," she said.