Merit Sloin
In the early 60s, Prof. Raphael Meshul from the Hebrew University isolated the active substance in hashish - THC. Its discovery led to the discovery of a large and complex system of endocannabinoids - substances similar to THC, which are produced in the body and participate in key processes.
A few years ago, Prof. Esther Shehmi and a team of researchers from the Hebrew University discovered that one of the endocannabinoids, found in high concentrations in the immune system and brain, is a natural protective substance that the brain produces after a head injury. The team found that in cases of brain trauma, the production of the endocannabinoid in the brain is significantly increased.
Another finding that was discovered when treating people who suffered a head injury is that in these patients very large amounts of bone tissue are produced after the injury, until there is sometimes a need to thin the bone. This finding, for which no satisfactory explanation was found at the time, and the finding of Prof. Hami were not related to each other, but Prof. Itai Bab from the bone laboratory at the Hebrew University and a team of researchers who worked with him discovered a close connection between the two. According to their new research, endocannabinoids not only protect the brain, but also maintain bone density. Therefore, it may be possible to use these substances as the basis of a drug that will prevent the thinning of bone tissue in osteoporosis patients.
Prof. Babb investigates the relationship between brain, behavior and changes in the structure of the skeleton as part of a project funded by the "Bikura" program of the Israel National Science Foundation. "Our interest in the subject began after the discovery that inside the bones there is a dense network of nerve cell extensions. This finding led us to think that the brain is related in some way to the activity of the bone. To test this, we looked for factors common to bone and brain, and among other things, we decided to test the relationship between endocannabinoids and bone tissue."
It is known that endocannabinoids work in the body by binding to two receptors - CB1 and CB2. The CB1 receptor is found in the nervous system and is responsible for the psychoactive effects of the active substances in hashish. The CB2 receptor is found in the immune system, it has no psychoactive activity and the information on its physiological function has been scarce until now.
"To check if the endocannabinoids work in the bone, we looked in the bone tissue for the receptors to which they contact," says Babb, "and the test revealed that CB2 receptors are actually present in large quantities." The next step was to find out what role endocannabinoids play in bone tissue. The team of researchers, which also included Prof. Shehmi from the Brain Trauma Research Laboratory, Prof. Meshulam from the Department of Medicinal Chemistry, doctoral students Or Ofek, Verdit Krem and Yossi Tam and graduate student Mirav Fogel, worked in collaboration with Prof. Andreas Zimmer and Dr. Malia Karsek from the University of Bonn, who created genetically modified mice in which the CB2 receptor is missing.
When the Hebrew University researchers examined the skeleton of the transgenic mice, it became clear that the mice developed a very severe osteoporosis disease that worsened as they aged. Osteoporosis is the most common degenerative disease in the West. It manifests itself in a decrease in the density of the bones, their weakening and the formation of multiple fractures that can cause severe disability and even death.
To confirm the hypothesis that the CB2 receptor is essential for maintaining bone density, the researchers tested whether activation of the CB2 receptor would slow the loss of bone mass in mice with osteoporosis. Babb used the synthetic material HU308, which Prof. Meshulam produced in the laboratory a few years ago. HU308 binds only to the CB2 receptor and activates it. Because it does not bind to CB1 it has no psychotropic effect on the brain. According to the research findings, published this week in the journal "Proceedings of the National Academy of Sciences", activation of the CB2 receptor inhibited the deterioration of bone tissue.
Inside the bone are bone-building cells and bone-dissolving cells. In normal situations there is a balance between the processes of decomposition and construction and the bone mass remains constant. But there are situations where the breakdown of the bone prevails over the construction. This usually happens with advancing age.
The researchers found that CB2 receptors are found both on the bone-destroying cells and on the bone-building cells. When the receptor is activated in the bone-destroying cells, their activity decreases; When activated in bone-building cells, their activity is increased. CB2 therefore has a dual activity: it both increases bone building and inhibits its destruction. Therefore, it is possible that substances that activate the receptor could serve as a basis for the development of drugs for osteoporosis patients.
Most of the existing drugs for osteoporosis prevent bone loss. There is only one drug to restore depleted bone, but it is given by daily injection. The researchers hope that HU308 can serve as a basis for creating a medicine that will be given in a tablet and will be used both to prevent bone loss and to restore bone that has already been lost.
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