Protein at Origins of Gum Disease and Osteoporosis Identified

“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,” says Baohong Zhao, PhD, lead author of the study and a research fellow in the Arthritis and Tissue Degeneration Program at Hospital for Special Surgery, New York.

Zhao completed the research—initiated at Showa University, Tokyo—in New York as he extended the study to human cells during the past year.

The researchers discovered that downregulation of IRF-8 increases the production of osteoclasts. However, enhanced development of osteoclasts, can create canals and cavities that are hallmarks of periodontitis and other bone diseases.

Previous researchers have devoted research to identify genes that are upregulated during enhanced development of osteoclasts, such as NFATc1, but few studies have identified genes that are downregulated in the process. To fill this knowledge gap current research employed  microarray technology to conduct a genome-wide screen to identify genes that are downregulated during the formation of osteoclasts. Researchers found that expression of IRF-8 was reduced by 75 percent 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 (computed tomography) 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 because of an increased number of osteoclasts. The researchers concluded that IRF-8 suppresses the production of osteoclasts.

Tests in human cells confirmed these findings. This included a study that showed that silencing IRF-8 messenger RNA in human osteoclast precursors with small interfering RNAs resulted in enhanced osteoclast production. In other words, decreased IRF-8 means more osteoclasts are produced.

This led the investigators to examine the effect of IRF-8 on the activity of a protein called NFATc1 previously reported to interact with IRF-8. They found that IRF-8 inhibited the function and expression of NFATc1. This makes sense given that upregulation of NFATc1 is involved in triggering osteoclast precursor cells to turn into osteoclasts.

“This is the first paper to identify that IRF-8 is a novel key inhibitory factor in osteoclastogenesis,” Zhao explains. “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.”