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Osteoporosis Clue Found In Stem Cell Signalling Protein

Understanding how a well-known signalling protein influences whether bone marrow stem cells turn into bone or fat could transform scientists' view of osteoporosis and lead to new treatments for the bone-thinning disease.

These are the implications of a new study led by Harvard Medical School (HMS) that was published online in The Journal of Clinical Investigation on 13 August.

Senior author Bjorn Olsen, Hersey Professor of Cell Biology at HMS, told the press about what they found:

"It shifts the thinking about what controls the differentiation of stem cells to bone cells instead of fat cells, and how to make sure this mechanism stays active with aging."

Bone is not a dead material: it is living tissue that is changing all the time, as it is continuously formed and reabsorbed.

Osteoporosis is a common bone disease where bone tissue becomes progressively thinner, resulting in higher risk of fracture. It affects about 1 in 5 American women and is thought to be caused by stem cells that normally differentiate into bone-forming cells becoming fat cells instead over time.

For the study, Olsen, who is professor of developmental biology and dean for research at Harvard School of Dental Medicine, and colleagues, decided to investigate the role of vascular endothelial growth factor, or VEGF, a common signalling protein that plays a key role in the development of blood vessels that are important in early bone growth and skeletal maintenance in mammals. The protein works by activating receptors on the surface of cells. Genetically Engineered Mice Lacking VEGF As a first step, the researchers genetically engineered lab mice that lacked the ability to make VEGF in their bone marrow stem cells.

Soon after they were born, the mice's skeletons began to show osteoporosis-like qualities, such as reduced bone tissue and a build up of fat in the bone marrow.

When the researchers isolated stem cells from the mice and grew them in culture, they found they were more likely to differentiate into fat cells than into bone-forming cells or osteoblasts.

To verify that it was the absence of VEGF that was producing this effect, the researchers disabled the VEGF in the stem cells of wild-type mice. They used a method known as RNA interference to do this.

The result was similar to the genetically engineered mice that lacked the ability to make VEGF, thus confirming that the protein was necessary for the stem cells to differentiate normally into bone-forming cells. Only VEGF Produced Inside the Stem Cells Works However, it was not clear in what way VEGF affected the stem-cell differentiation process. Would simply bathing the cells in the VEGF that they were not secreting be enough to stimulate normal differentiation into bone-forming cells?

But when they added VEGF protein to the cells in the stem cell culture from the engineered mice, the researchers found it did not restore normal differentiation.

So, perhaps it is not having the VEGF around that matters, but the fact that it is made inside the stem cells.

To test this, the researchers re-introduced the missing genetic code for producing the protein into the nuclei of the cells in the cell culture (they did this by inserting a virus carrying the missing bit of code).

It worked: once the cultured stem cells received the missing genetic code for making VEGF, they starting making VEGF protein and differentiating into bone-forming cells at rates similar to that of normal cells.

This suggests that the ability of bone-marrow stem cells to differentiate into bone-forming cells needs VEGF that is made inside the cells.

The researchers confirmed this rather unexpected results with additional biochemical and control experiments.

From further experiments, they also established that VEGF controls molecules that are important for bone formation and fat cell differentiation, and it also regulates a protein in cell nuclei that is thought to play a role in premature aging. What Next? Olsen and his team now want to find out more about VEGF signalling pathways in bone marrow stem cells, and identify targets for drugs.

He told the press if they could better understand the signalling mechanisms and find out which parts of them to target to increase VEGF production inside the cells, then perhaps that would open potential routes for new therapies for osteoporosis.

NIH grants and funds from a Harvard School of Dental Medicine Dean's Scholarship helped pay for the study.

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