Bones that refuse to heal may one day be set straight by a drug that stimulates the growth of new blood vessels, according to new research from the University of California, San Francisco. So far, however, the growth factor drug has been tested only in mice, and it could be years before it is used in hospitals.
These results were presented at this week's annual meeting of the Orthopaedic Research Society, in Orlando, Florida.
As cancer and cardiology researchers already know, VEGF, or vascular endothelial growth factor, promotes blood vessel growth. Oncologists at a few biotech companies are running clinical trials of anti-VEGF drugs to reduce the flow of blood to tumors. Cardiologists are studying whether VEGF can sprout new blood vessels to bypass blocked arteries in patients with inoperable heart disease.
Blood vessel growth, known as angiogenesis, is also thought to help deliver the chemicals needed for bone cells to rebuild after a fracture, says Jill Helms, PhD, DDS, assistant professor of orthopedic surgery at UCSF. "Vascular invasion is one of the critical steps of bone repair," said Helms, who collaborated with Zena Werb, PhD, a professor of anatomy at UCSF.
While most broken bones will repair to their original strength within a matter of weeks, some breaks stubbornly refuse to heal for months, years, or longer, she said. Scientists have suggested a few factors that may interfere with bone healing, such as nutrition, illnesses such as diabetes, and damage to soft tissue surrounding the bone. Helms and her colleagues suspected that soft tissue damage interrupts proper blood flow to the fracture, and that proteins that encourage angiogenesis, such as VEGF, might help to heal these stubborn breaks.
To test VEGF as a possible treatment, Helms' team worked with 20 mice with broken limbs that were being treated with pain-relieving drugs. After splinting the legs of these mice, the researchers shifted the splint each day to a different position, a procedure that prevents healing growth of new bone, presumably by destroying the newly forming networks of blood vessels.
Manipulating these tiny splints consistently and accurately was a challenging technical feat, Helms said. "It requires people with great hands," she said, such as Diane Hu, MD, the staff specialist who perfected the technique.
After 10 days of this treatment, x-rays showed that only cartilage and other fibrous cells grew in the gap, or interzone, between the pieces of broken bone.
Helms and her colleagues then injected doses of VEGF into the interzones of 10 broken mouse legs, and made sham injections to 10 others. After ten days of splint-shifting, the researchers could see osteoblasts, or bone growth cells, developing in interzones of the mice injected with VEGF. The sham-injected mice still had only fibrous tissue growth. The VEGF-injected mice also had much higher expression of the gene Cbfa1, which is thought to help stimulate formation of new osteoblasts.
Although more research is necessary, VEGF treatment could help to give a happy ending to the tragic stories of patients who suffer from non-bony healing, said Ted Miclau, MD, an orthopedic surgeon who works in Helms' lab. "The fractures that tend not to heal are open fractures and those from high energy accidents, such as high speed auto, or pedestrian vs. auto accidents,' he said.
In addition to studying VEGF's role in bone healing, Helms' lab is examining whether it might also be important in embryonic bone growth. They have begun injecting either VEGF or inhibitors of VEGF into the limbs of embryonic chickens as they develop in the egg. They will then examine the effects of too little or too much VEGF on skeletal development.
Other researchers collaborating on the project were UCSF orthopaedic surgery residents Mark Lee, MD, and Christian Oglivie, MD, post-doctoral fellow Celine Colnot, PhD, and Thiennu Vu, MD, PhD, a UCSF assistant professor of medicine.