Identification of regulatory mechanism could lead to new treatments of osteoporosis

Jan 2 2006

Substance reduces bone loss in mice

Medical researchers at the University of Bonn, working in collaboration with scientists from Israel, the USA and Britain, have identified a previously unknown regulatory mechanism in the process of bone loss. Their findings could open up new approaches to the treatment of osteoporosis. More than four million people, predominantly women, are estimated to suffer from this distressing illness in Germany alone. In recognition of the importance of her results, Dr. Meliha Karsak from the Bonn-based Life & Brain Center has recently been awarded the Osteology Prize of the German Society for Endocrinology, which entails a cash award of 8,000 euros. Her study will now be published in the renowned "Proceedings of the National Academy of Sciences" (PNAS).

Working together with colleagues from the University of Jeruslam, Dr. Meliha Karsak found that mice with a particular gene defect have a lower bone density. This breakthrough is making "cannabinoidreceptors" a key focus of osteoporosis research.

"We know two types of cannabinoidreceptors, CB1 and CB2," explains Dr. Karsak. "The CB1 receptor is formed by nerve cells in the brain and is responsible for, among other things, the mental effect of cannabis. The CB2 receptor, on the other hand, does not occur in nerve cells; its function was previously unknown." To explore this function the scientists working with Bonn's senior brain expert Professor Dr. Andreas Zimmer have made genetic modifications in mice in order to switch off their CB2 receptor. Dr. Karsak summarises what happened: "The animals gradually lost their stabilising trabeculae. We found in these mice that the number of osteoclasts – special cells that can break down the bone tissue –increases by almost 50 per cent."

Signal molecules regulate bone density

Together with a research group from Israel and England, Dr. Karsak was able to demonstrate that osteoclasts, as well as their opposite number, the osteoblasts, which are responsible for building bone, carry CB2 receptors on their surface. In this way it appears that signal molecules like the endocannabinoids being formed by the body are able to regulate bone growth.

This thesis has been supported by experiments on mice whose ovaries were removed. The resulting oestrogen deficiency would normally lead to a depletion of bone material and finally to "mouse osteoporosis". "We treated these mice with an active substance that bonds specifically to the CB2 receptor. In this way we were able to diminish the bone loss caused by ovary removal," explains the molecular biologist.

Many patients carry a particular variant of the CB2 gene

But how far can these results be applied to human beings? To answer this question, Dr. Karsak turned to a team of scientists working in France who had access to genetic samples from more than 160 female osteoporosis patients and 240 healthy women. This line of enquiry proved a complete success: "We found that a specific variant of the CB2 gene occurs more frequently among the patients than among the healthy control group," says Dr. Karsak. Individuals who carry this defect in their genetic make-up are not destined to have problems. However, as she points out, "Women with this mutation have a three-fold higher risk of osteoporosis."

The results show not only that the CB2 receptor is essential for the maintenance of a normal bone mass; they also open up completely new possibilities for therapy: "In many women with osteoporosis the CB2 receptor functions, so in their cases the disease has other causes. For them we could consider stimulating the receptor through medication and in this way slow down their bone loss." The possibility that this approach can work has been demonstrated by the experiments on mice without ovaries.

The findings hold out hope for women with a CB2 defect, too. First, it is easy to identify whether a woman is carrying the relevant mutation, so the results promise improved and faster diagnosis. Second, they have drawn attention to a previously unknown regulatory mechanism, making it a focus of osteoporosis research. Here lies the chance of developing new medicines in the long-term.