ROCHESTER, New York—Tumor necrosis factor alpha (TNFα) decreases osteoblast numbers via an enzyme called Smad Ubiquitin Regulatory Factor 1 (SMURF1), which shuts down two proteins that would otherwise drive bone formation, according to a new murine study that shines a light on how rheumatoid arthritis (RA) destroys bone. The findings are published in the August 22 edition of the Journal of Biological Chemistry.1

“We identified a specific target and then we can develop a small molecule inhibitor to shut down the action of SMURF1 and its relatives and give it to patients with RA and osteoporosis to inhibit bone loss.”—Lianping Xing, PhD
“We identified a specific target and then we can develop a small molecule inhibitor to shut down the action of SMURF1 and its relatives and give it to patients with RA and osteoporosis to inhibit bone loss,” Lianping Xing, PhD, an assistant professor of pathology and laboratory medicine at the University of Rochester Medical Center in NY, told MSKreport.com.

The implication of the discovery is that TNF blockers may also help stop bone loss in RA.

Murine study IDs SMURF1 as key player in RA bone loss

The researchers generated two groups of mice including one with high TNFα levels with SMURF1 present, and another with high TNFα production, but no SMURF1. Using imaging technologies, the team measured and compared bone volume and strength. The increased TNFα levels dramatically decreased the levels of Smad1 and Runx2—two proteins believed to increase the number of osteoblasts—but only if SMURF1 was present to pass on the signal from TNFα.

Genetically engineered mice with the SMURF1 gene removed no longer responded to TNFα because SMURF1 was not present to label Smad1 and Runx2 with the ubiquitin destruction tag, the study showed. The mice with increased TNFα had lesser bone mass than their counterparts. This was partially reversed in mice where SMURF1 had been removed.

Going forward, the researchers will be looking at the effect of the cancer drug bortezomib (Velcade®) to see if shutting down proteosomes in bone cells increases bone mass in mice engineered to have high levels of TNFα. Bortezomib is a general proteosome inhibitor. It does not specifically target SMURF1.

Reference
1. Guo R, Yamashita M, Zhang Q, et al. Ubiquitin ligase SMURF1 mediates tumor necrosis factor induced systemic bone loss by promoting proteasomal degradation of bone morphogenetic signaling proteins. J Biol Chem. 2008;34:23084-23092.