Boosting a Key Protein to Help Bones That Won’t Heal

The occasional bone fracture from a sports injury, motor vehicle accident, or just plain bad luck may seem commonplace in today’s world of advanced medical treatments. Yet, there is always the possibility that the break won’t heal properly or quickly – even with the aid of pins, plates, or a cast.

Scientists and physicians have unsuccessfully tried to overcome this potential problem through the administration of bone morphogenetic proteins (BMPs). These regenerative factors were initially designed to promote spinal fusion and bone repair, but studies found that the molecules can overperform, causing excessive or misdirected bone growth.

Now a collaborative team of investigators, led by scientists at the University of Michigan Medical School, have discovered a new molecule they believe will provide the assisted growth to bones that was originally intended using BMPs. Findings from the new study were published in npj Regenerative Medicine, in an article entitled “Intraoperative Delivery of the Notch Ligand Jagged-1 Regenerates Appendicular and Craniofacial Bone Defects.”

“Each year, 33% of US citizens suffer from a musculoskeletal condition that requires medical intervention, with direct medical costs approaching $1 trillion USD per year,” the researchers write. “Despite the ubiquity of skeletal dysfunction, there are currently limited safe and efficacious bone growth factors in clinical use.”

“Novel therapies have gone underdeveloped because of this assumption that bones heal without problem,” added senior study investigator Kurt Hankenson, D.V.M., Ph.D., a professor of orthopedic surgery at Michigan Medicine. “The reality is there’s a huge number of fractures that occur each year that don’t heal very well.”

Due to the limited number of options for aiding patients with bone healing, the research team began to look for novel approaches. What they attempted was the delivery of additional Jagged-1—a potent osteoinductive protein known to activate the Notch signaling pathway that regulates bone healing—at the spot of a bone injury.

“We’ve hypothesized for many years that by binding Jagged-1 to a biomaterial and delivering it to a bone injury site, we could enhance healing,” Dr. Hankenson stated.

Dr. Hankenson and his team’s assertions were correct. The researchers found that rodents who received Jagged-1, applied via wet collagen sponge, saw improvements to the skull and femoral bone injuries. Conversely, rodents treated with BMPs also benefited but developed the same problematic bone hypertrophy associated with human use of those proteins. These findings suggest that the Jagged-1 therapy could one day benefit many patients.

It’s not fully known why some bones don’t heal the way they should – nor do scientists know whether a genetic component plays a role. However, it is known that individuals with metabolic dysfunction, such as diabetes, have greater odds of poor healing after a fracture. The same holds true for the elderly, who are also prone to more bone injuries because of lower bone mass, such as osteoporosis. Those suffering severe trauma, regardless of age or prior health status, also are likely to face problems.

Dr. Hankenson and his colleagues have been studying for some time the capacity of the Jagged-1 ligand to promote bone-forming cells. The scientists found that the signaling is unique, since this particular ligand typically binds to a delivery cell to activate bone healing in an adjacent cell – a vital trait to help ensure that a supplemental Jagged-1 dose, administered at the spot of injury, stays in place (and on task) to carry out its intended function. As a result, “bone will only form where bone is supposed to form,” Dr. Hankenson remarked.

BMPs, by comparison, are soluble, so they can migrate from the site of delivery and settle elsewhere in the body, triggering other cells that aren’t supposed to form bone. Moreover, because the body produces Jagged-1 on its own, this potential new therapy would require a synthetic version of the ligand to be produced and administered to a patient.

“We do not think there is necessarily a deficiency,” concluded Dr. Hankenson. “But when we think about biological molecules delivered for therapy, we’re usually identifying something that’s there normally and trying to promote more activity by giving more of it.”