Researchers from Stanford University School of Medicine in Palo Alto, CA, have discovered a protein that stimulates the stem cells, promoting bone regeneration after fractures in mice with diabet. This discovery may help in the treatment of unhealed fractures in people suffering from diabetes. The results were published January 11 in the journal Science Translational Medicine.
“We’ve uncovered the reason why some patients with diabetes don’t heal well from fractures, and we’ve come up with a solution that can be locally applied during surgery to repair the break.” – sums up the work Michael T. Longaker, a professor of plastic and reconstructive surgery and one of the study’s senior authors.
Diabetes is a chronic disease that occurs when the body’s ability to produce or respond to insulin – a hormone that regulates blood sugar – is impaired.
Today, there are over 420 million people with diabetes around the world – almost four times more than there were in 1980 (108 million).
Raised blood sugar (hyperglycemia) is the result of uncontrolled diabetes, which over time can lead to damage of many organs, including the cardiovascular system, eyes, kidneys and others. One of the complications of diabetes is problematic bone healing.
In their investigation, Prof. Longaker and his group observed a decrease in activity of stem cells in bone diabetic mice as well as in bone samples of diabetic patients who underwent surgery to replace joints. During the experiments, the researchers discovered a protein that stimulates stem cells. When they applied the protein to bone fracture sites in the mice, it increased expression of key signaling proteins and enhanced healing in the animals.
The new study were based on the previous work of scientists, which have been identified and described a population of cells in the bones of mice, which function as skeletal (mesenchymal) stem cells (SSCs). These adult stem cells have great potential to become components of the skeletal system, including bone tissue, cartilage and stroma – a part of the bone marrow.
Further investigation revealed that the deterioration in the recovery of fractures in mice is associated with low levels of SSC.
This discovery prompted scientists to think about the problems with skeletal stem cells in diabetic patients with poorly healing fractures.
In the new study, the team used a mice bred to develop type 2 diabetes when they reached approximately 4 weeks of age.
All animals showed normal fracture healing until disease developed. However, after disease onset, restored bone was significantly weaker and have a lower density than the bones of healthy mice.
Researchers also noted that diabetic animals had significantly lower numbers of SSCs in healing bone tissue 7 days after fracture than normal mice.
After a series of experiments conducted by the researchers found that the stem cells themselves worked fine, and there were no systemic causes of their decline. Scientists have suggested that the reason is problems with the signals that cells obtained from the environment (niche).
A closer look showed that diabetic mice, produced less “hedgehog” signaling proteins, which are known to play an important role in embryonic development, tissue regeneration, and other key biological processes.
Scientists have shown that blocking the hedgehog signaling pathway in mouse without diabetes leads to the fact that the bone at the fracture site after the wound become fragile and thin, as in diabetic animals.
In addition, the researchers found that the addition of hedgehog proteins in the diabetic mice niche stem cells restores their ability to the normal healing of fractures.
In the final series of experiments, the team worked with samples of bone diabetics and non-diabetic patients who underwent joint replacement in osteoarthritis.
The investigators compared the expression of proteins in the samples, which play an important role in the signaling pathway hedgehog. They found the same results as in the experiment with mice. In bone tissue samples of patients with diabetes, the level of protein expression signal was extremely low.
Scientists decided to find out – whether the reduction in the activity of the signal path with an increased level of tumor necrosis factor-alpha (tumor necrosis factor alpha, TNF-alpha) associated observed in diabetics.
Experiments conducted in mice have shown that high levels of TNF-alpha inhibit the expression of several proteins signaling pathway hedgehog. However, a complete “off» TNF-alpha can lead to serious consequences, as it plays a key role in many biological processes.
“We have developed a possible strategy for the elimination of tissue-specific disease, which does not allow to effectively treat fractures, With complex metabolic diseases such as diabetes. Our method relies on the local application of a compound that stimulates the activity of adult stem cells. We believe that the hedgehog-mediated molecular therapy aimed directly at patients with stem cells, can used in the treatment, “- said Longaker.