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Researchers identify protein involved in causing gum disease, osteoporosis, arthritis
Date:8/30/2009

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, scientists at Hospital for Special Surgery, collaborating with researchers at other institutions, 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 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 that was 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 [production of osteoclasts]," said Dr. Zhao. "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 futur
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Contact: Phyllis Fisher
fisherp@hss.edu
212-606-1197
Hospital for Special Surgery
Source:Eurekalert

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