Signaling Molecules May Limit Bone Destruction and Bone Loss from RA

Researchers have discovered a new way to use the role of signaling molecules to inhibit another complex that plays a key role in the ‘turning on’ of genes “that cause the stem cell precursors of osteoclasts to mature and start eating bone,” a discovery that may lead to the formation of new rheumatoid arthritis and osteoporosis drugs.

Researchers from the University of Rochester Medical Center have discovered a new way to use the role of signaling molecules to inhibit another complex that plays a key role in the ‘turning on’ of genes “that cause the stem cell precursors of osteoclasts to mature and start eating bone,” a discovery that may lead to the formation of new rheumatoid arthritis (RA) and osteoporosis drugs.

In diseases that erode bone, the signaling molecules TNF α and RANKL cause too much bone breakdown, according to Zhenqiang Yao, Lianping Xing, and Brendan Boyce, MD. The team found that, when TNF α and RANKL were turned off, the nuclear factor kappa B complex (NF-κB) which turn on the genes that signal osteoclasts into action was increased by TNF α , but decreased by RANKL. In other words, for the mice the researchers used in the study, those who had had their TNF α signal molecule inhibited experienced greater bone loss and damage than the mice whose RANKL signal molecule was inhibited. According to the researchers, “TNF α, but not RANKL, also increased levels of a protein in osteoclast precursors called TNF receptor-associated factor 3 (TRAF 3), which may help NF-κB p100 block osteoclast formation and inflammation.”

“While further studies will be required to confirm and detail this mechanism, our results argue strongly that increasing levels of either TRAF3 or NF-κB p100 could represent a powerful new way to limit bone destruction and inflammation-induced bone loss seen in osteoporosis and rheumatoid arthritis,” said Boyce. “NF-κB p100 levels may vary with each person’s genes, making some more susceptible to TNF α-driven disease. Future solutions may include local delivery of p100 into diseased joints via gene therapy, or targeting with a drug the enzyme, NIK, which otherwise limits the p100 supply.”

Findings of the study were published in the Journal of Clinical Investigation.