Stop the loss

The discovery of an inhibitor of the production of bone-resorptive cells opens new possibilities for regulating bone loss.The work is important because an excess of osteoclasts has been implicated in diseases like osteoporosis, rheumatoid arthritis and bone cancer.

A RIKEN-led research group has discovered that the methyl form of a small molecule—first found in fungi—inhibits production of the bone resorptive cells known as osteoclasts. And by immobilizing the compound on gel beads, the researchers have begun to unravel the biochemical mechanism involved.

The work is important because an excess of osteoclasts has been implicated in several significant human diseases including osteoporosis (Fig. 1), rheumatoid arthritis and bone cancer. An inhibitor to the production of osteoclasts might be useful for developing drugs to treat such conditions. The compound the researchers found, methyl-gerfelin (M-GFN), also can be employed to probe how osteoclasts differentiate and function.

Osteoclasts develop from bone marrow-derived macrophages in the presence of factors released by bone-forming osteoblasts. The two cell types work in tandem to build, model and renew bones. But an oversupply of osteoclasts can break down bone inappropriately, leading to bone disease.

In a recent paper in Proceedings of the National Academy of Sciences1, the research group from the RIKEN Advanced Science Institute in Wako together with colleagues from three Japanese universities detail how they used an assay involving the differentiation process to screen small molecules from the chemical library of the RIKEN Natural Products Depository for inhibitors. They found that while GFN had a weak inhibitory effect, M-GFN suppressed osteoclast differentiation in a dose-dependent manner. The difference between the compounds appears to be in their ability to be absorbed by cells.

The researchers then attached M-GFN to agar gel beads by means of a linker activated by light—a process which they had developed earlier—and exposed the beads to macrophage breakdown products. Two of the proteins bound directly to M-GFN.

They then suppressed the activity of the genes coding for those two proteins using RNA interference techniques, and found that one of them, the antioxidant enzyme glyoxalase I (GLO1), was required for production of osteoclasts. By analyzing the crystal structure of the complex that forms between M-GFN and GLO1, the researchers were able to show that M-GFN inhibits its function by binding to its active site.

“M-GFN might be useful as an anti-resorptive agent if it has pharmacological activity. We plan to examine the activity of M-GFN in live mice, particularly in mouse models of osteoporosis,” says the paper’s lead author, Makoto Kawatani. “We are also looking at creating compounds with stronger inhibitory activity based on the structure we see in the GLO1/M-GFN complex.”


1. Kawatani, M., Okumura, H., Honda, K., Kanoh, N., Muroi, M., Dohmae, N., Takami, M., Kitagawa, M., Futamura, Y., Imoto, M. & Osada, H. The identification of an osteoclastogenesis inhibitor through the inhibition of glyoxalase I. Proceedings of the National Academy of Sciences USA 105, 11691–11696 (2008).

The corresponding author for this highlight is based at the RIKEN Antibiotics Laboratory

Published: 21 Nov 2008


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Websites: Link to article on RIKEN Research Figure 1: Bone affected by osteoporosis is thinner and less dense than normal and more prone to fracture RIKEN Antibiotics Laboratory


Proceedings of the National Academy of Sciences USA 105, 11691–11696 (2008)