Possible Path To Improved Bone-repair Procedures Discovered

A new therapeutic approach helps improve bone healing by binding a protein called Jagged-1 to a biomaterial and is delivered into the bone injury site.

When a patient breaks a bone, there's a possibility the fracture won't heal properly or quickly even with the aid of pins, plates or a cast. And use of another restorative tactic known as bone morphogenetic proteins (BMPs) is increasingly less likely. Designed to promote spinal fusion and bone repair more than a decade ago, these molecules can overperform, causing excessive or misdirected bone growth, studies have shown.

‘Experiments with adding a heparin mixture with clinically relevant levels of bone morphogenetic protein lead to significant reductions of ossification in preclinical and computer modeling.’

But because bone-healing biological research has often been limited, few other options exist. "Novel therapies have gone underdeveloped because of this assumption that bones heal without problem," says Kurt Hankenson, D.V.M., Ph.D., a professor of orthopaedic surgery at Michigan Medicine.

"The reality is there's a huge number of fractures that occur each year that don't heal very well." The divide recently inspired Hankenson and a team of scientists from other institutions to examine a new therapeutic approach. Their method: deliver 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 the Jagged-1 to a biomaterial and delivering it to a bone injury site, we could enhance healing," Hankenson says.

The results, published in npj Regenerative Medicine, affirm that hunch: Rodents that received Jagged-1, applied via wet collagen sponge, saw improvements to skull and femoral bone injuries.

Rodents treated with BMPs, by contrast, also benefited but developed the same problematic bone hypertrophy associated with human use of those proteins. Those findings suggest that the former therapy could one day benefit people.

It's not fully known why some bones don't heal the way they should or do scientists know whether a genetic component plays a role, Hankenson says.

This much is clear: People with metabolic dysfunction, such as diabetes, have greater odds of poor healing after a fracture. So do 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.

What Hankenson and other research groups have studied for years, meanwhile, is the capacity of the Jagged-1 ligand to promote bone-forming cells.

The signaling is unique, Hankenson says, because 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," says Hankenson.

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. 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.