Interferon Regulator Factor-8

Orthopaedics Today

Researchers identify protein involved in causing osteoporosis, arthritis

1^st on the web (August 31, 2009)

Investigators at the Hospital for Special Surgery in New York, along with several collaborators, reported that a gene called interferon regulator factor-8 (IRF-8) plays an important role in the development of diseases such as rheumatoid arthritis, osteoporosis and periodontitis (gum disease).

The study, which appeared online Aug. 30 ahead of print in the journal Nature Medicine, could lead to new treatments, according to the authors.

“The study doesn't have immediate therapeutic applications, but it does open a new avenue of research that could help identify novel therapeutic approaches or interventions to treat diseases such as periodontitis, rheumatoid arthritis or osteoporosis,” Baohong Zhao, PhD, lead author of the study and a research fellow in the Arthritis and Tissue Degeneration Program at the Hospital for Special Surgery, said in a press release.

Zhao initiated the study while working in the laboratory led by Masamichi Takami, PhD, and Ryutaro Kamijo, PhD, at Showa University, Tokyo, where much of the work was performed. Zhao completed the study and extended the work to human cells during the past year at the Hospital for Special Surgery while working with Lionel Ivashkiv, PhD.

Specifically, the researchers discovered that downregulation of IRF-8 increases the production of cells called osteoclasts that are responsible for breaking down bone. Enhanced development of osteoclasts can create canals and cavities that are hallmarks of diseases such as periodontitis, osteoporosis and rheumatoid arthritis.

Previous researchers have spent time identifying genes that are upregulated during enhanced development of osteoclasts, such as NFATc1, but few studies have identified genes that are downregulated in the process, according to the press release.

To fill this knowledge gap, the researchers used microarray technology to conduct a genome-wide screen to identify genes that are downregulated during the formation of osteoclasts. They found that expression of IRF-8 was reduced by 75% in the initial phases of osteoclast development. The researchers then genetically engineered mice to be deficient in IRF-8 and gave the animals X-rays and CT scans to analyze IRF-8's influence on bone.

They found that the mice had decreased bone mass and severe osteoporosis. Experiments demonstrated that this was due not to a decreased number of osteoblasts but rather due to an increased number of osteoclasts. The researchers concluded that IRF-8 suppresses the production of osteoclasts.

Tests in human cells confirmed these findings, Zhao noted.

“This is the first paper to identify that IRF-8 is a novel key inhibitory factor in osteoclastogenesis [production of osteoclasts],” Zhao said in the press release. “We hope that the understanding of this gene can contribute to understanding the regulatory network of osteoclastogenesis and lead to new therapeutic approaches in the future.”