Gene therapy converts dead bone graft to new, living tissue 18/2/05. By the University of Rochester Medical Center Converting foreign bone splints to living bone in mice may lead to help for cancer and trauma patients who suffer with fragile and failing bone grafts.

Researchers at the University of Rochester Medical Center have created a way to transform the dead bone of a transplanted skeletal graft into living tissue in an experiment involving mice. The findings were published in Nature Medicine.

The procedure, designed by a team led by Edward Schwarz, associate professor of orthopedics and of microbiology and immunology, is intended to eventually aid people with various cancers or injuries whose treatment involves the replacement of large sections of bone.

Cancers such as osteosarcoma, one of the most common types of bone cancers, or tumors that occur adjacent to bones, often must be treated by removing the diseased section of bone and replacing it with the only alternative available - a donated section of comparable bone from a cadaver. The new splint of bone is then screwed into place, giving the patient most of the strength and support of the original bone. Bone, unlike any other tissue in the human body, can still perform one of its functions, structural support, even if all its cells are completely dead. A serious problem arises, however, when the bone wears over time.

"Everyday activities cause microscopic fractures in our bones," explains Schwarz. "Those fractures are normal and healthy, and our bones re-knit them constantly. But when the bone is dead, there is no healing, and those tiny fractures begin to accumulate until finally, perhaps in ten years, the implanted section collapses, and more drastic surgery becomes necessary."

His team replaced sections of bones in dozens of mice, using both healthy and dead segments, and found that the genes that create two key proteins in living bone, called RANKL and VEGF, were barely expressed around the dead bone. He then modified a harmless virus to carry these genes, devised a method of freeze-drying a paste containing the virus so it could be easily handled, and painted it directly onto a bone graft during surgery.

The virus permeated the inflammatory tissue around the dead bone and turned on the genes. The mouse body then began to treat the implanted bone as if it were its own tissue instead of a foreign object, which would normally trigger the body to wrap the 'invader' in scar tissue.

"That recognition is the key," says Schwarz. "It's at that point that the body actually begins changing the dead, foreign bone splint, into the body's own, whole, living bone."

Schwarz's studies with mice showed their dead splints were quickly converted to new, healthy bone. He projects that the bone would be completely converted in just a year, and that a human bone might be completely converted in as little as five years.

"We're very excited about the prospects of this technology," says Schwarz. "Our ultimate goal is to apply this to one of the Holy Grails of orthopedics - cartilage repair. Unlike bone, damaged cartilage, even in a healthy person, can't re-grow or repair itself."

Adapted from a news release by the University of Rochester Medical Center.

Image credit: Professor Alan Boyde

Further reading

Ito H, et al. Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy. Nat Med 2005 Mar;11(3):291-7. Abstract