A new approach to the debilitating bone loss disease, osteoporosis, could be on the horizon thanks to research by Andreas Zimmer and Meliha Karsak from the Bonn-based Life & Brain Center in Germany and collaborators in Israel, the UK, and the USA. The researchers have discovered a regulatory mechanism involved in bone loss linked to a chemical receptor in our bodies with a previously unknown function, which could lead to a new treatment.
Bone comprises a thick outer shell and a strong inner mesh filled with the protein collagen, calcium salts and other minerals. The spaces in this honeycomb-like structure are pervaded by blood vessels and bone marrow. Osteoporosis occurs when the holes between bone become bigger, making it fragile and liable to break easily. Osteoporosis usually affects the whole skeleton but it most commonly causes breaks (fractures) to bones in the wrist, spine, and hip, with an estimated 10 million sufferers in the US alone.
Substances made in the body called endocannabinoids are composed mainly of fatty acids which were discovered during the last 15 years. The fatty acid anandamid was discovered by Raphael Mechoulam of the Hebrew University in 1992. These substances bind to and activate two receptors, CB1 and CB2. The first is found in the nervous system and is responsible for the psychoactive effects of the active components in the cannabis plant and endocannabinoids. The second receptor is found in the immune system. It is not known to be involved with psychoactive responses, and there has been little information about its physiological function.
Karsak’s findings, published in the journal Proceedings of the National Academy of Sciences, suggest that there might be a new way to handle osteoporosis. “We know two types of cannabinoid receptors, CB1 and CB2,” she 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 try and uncover the role of CB2, the scientists working with the University of Bonn’s senior brain expert Professor Dr Andreas Zimmer discovered that mice lacking a functioning CB2 receptor have an increased number of so-called osteoclasts, special cells that break down bone tissue. They then demonstrated that osteoclasts, as well as their bone-building counterparts, osteoblasts, carry CB2 receptors on their surfaces. This suggests that the body’s natural cannabinoids, endocannabinoids, regulate bone growth.
With this information in hand, Karsak and colleagues 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. “We found that a specific variant of the CB2 gene occurs more frequently among the patients than among the healthy control group,” says 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. Karsak adds, “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.”
Indeed, the Hebrew University researchers have now developed a new synthetic compound, HU-308, which activates CB2 and slows the development of osteoporosis in mice. This compound forms the basis for a cannabinoid-based, anti-osteoporotic type drug which has also been found to be free of any psychoactive side effects.