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A protein ties osteoporosis to high blood sugar and the spread of cancer to the bone
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“It all began with a discovery that was made entirely by chance,” says Prof. Yehiel Zick of the Weizmann Institute’s Molecular Cell Biology Department. He is referring to a large research project in his lab that may lead to new ways of developing therapies for osteoporosis, diabetes and prostate cancer. But its original aim was completely different.
Some twenty years ago, Zick intended to clone a certain protein for a study being conducted in his lab on insulin resistance. In one stage of the process, an antibody that was meant to identify the protein accidentally picked out a different, previously unknown molecule. The molecule’s DNA sequence soon revealed that it belonged to the family of lectins, sugar-binding proteins that more than a hundred years ago were discovered in plants and for many years were used in blood typing: Red blood cells can be classified by type via the sugar molecules on their surfaces, which, in turn, can be identified by different lectins. We now know that a number of lectin families also exist in animals.
The protein Zick discovered in his lab in 1995 belongs to the galectin family of animal lectins. Zick wasn’t sure exactly how many new galectins were already in the process of being identified at the time, so to be on the safe side he named the newly isolated molecule galectin-8.
He went on to study the properties of galectin-8 and, several years ago, with Dr. Yaron Vinik, then a Ph.D. student in his lab, he developed a mouse whose genes had been engineered to produce excessive amounts of this protein. The scientists hoped that abnormalities in the mouse could help them reveal the properties of galectin-8, but the mouse appeared to be entirely normal. Another avenue of research offered a solution: With the help of a chip that measures the amounts of mRNA – the messenger molecules of different proteins – they found that galectin-8 took part in regulating genes involved in bone remodeling, prompting them to study the protein’s effects on this process.
As reported recently in eLife, they have now determined exactly how galectin-8 affects bone remodeling. It turned out that this protein stimulates the production of a signaling substance called RANKL, which regulates bone turnover by creating a dialogue between bone-building cells called osteoblasts and bone-destroying cells called osteoclasts. In fact, when the scientists applied galectin-8 to osteoblasts, these cells produced six times more RANKL than usual. And when they applied galectin-8 to osteoblasts that were cultured together with bone marrow in a laboratory dish, many more osteoclasts than usual were produced from the marrow’s stem cells. Finally, the researchers examined their genetically engineered mice by computer tomography and discovered that despite normal appearance, the animals had unusually low bone mass and brittle bones.
However, the loss of bone mass was not due simply to increased numbers of osteoclasts. Rather, the mice had a higher than normal bone turnover: Their osteoblast levels were also elevated, but the osteoclast levels were elevated even further, so that the end result was excessive bone loss. This finding is significant because that is precisely what happens in human beings with osteoporosis, which in turn suggests that galectin-8 is involved in this disease in humans and can therefore serve as a potential target for the future development of drugs for treating it.
But the effect galectin-8 has on bone is not limited to osteoporosis. Recent studies in Zick’s lab have shown that this protein stimulates the activity of genes that may facilitate the spread of prostate cancer to the bone. A better understanding of this process may help prevent this metastasis.
Finally, in experiments conducted in a laboratory dish and animal models, Zick’s team found that in addition to stimulating the production of RANKL, galectin-8 causes osteoblasts to release a number of inflammatory molecules that cause blood sugar levels to rise abnormally. Indeed, their genetically engineered mice with elevated galectin-8 levels were found to have high blood sugar.
With this finding, research launched twenty years ago in Zick’s lab has come full circle. It began with studies of insulin resistance, which often leads to type 2 diabetes, and may now open up a new avenue of research into mechanisms leading to diabetes.
Apart from Dr. Vinik, taking part in these studies are Hadas Shatz-Azoulay, Dr. Alessia Vivanti, Dr. Navit Hever, Dr. Yifat Levy, Rotem Karmona and Dr. Sigalit Boura-Halfon – all current or former students in Prof. Zick’s lab – as well as Dr. Vlad Brumfeld from Weizmann’s Chemical Research Support. The study was a collaborative work with the group of Prof. Itai Bab from the Hebrew University of Jerusalem, who sadly recently passed away.
Lectins and Galectins
Weizmann Institute scientists have a long tradition of studying lectins and galectins. For several decades, starting in the early 1960s, Prof. Nathan Sharon conducted pioneering studies on the properties of lectins. In one of the projects, he and Prof. Yair Reisner, his former student, found that lectins could be used to isolate subpopulations of immune cells called lymphocytes. Reisner, together with physicians at the Memorial Sloan Kettering Cancer Center, subsequently showed that certain lymphocytes separated out with the help of a soybean lectin could enable mismatched bone marrow transplantation in “bubble children” suffering from severe combined immunodeficiency. It was another Weizmann Institute researcher, Prof. Vivian Teichberg, who in the mid-1970s, for the first time, found a galectin in an animal: an electric eel.
Prof. Yehiel Zick's research is supported by the Yad Abraham Research Center for Cancer Diagnostics and Therapy, which he heads; the Adelis Foundation; the estate of Fannie Sherr; and Ayala Benjamin-Mashat, Switzerland. Prof. Zick is the incumbent of the Marte R. Gomez Professorial Chair.
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