A Salamander’s Secret Could Help Heal Future Fractures Faster

A series of biochemical reactions at play when a salamander regrows its limbs have been identified to help catalyse the healing of broken bones – but within some important limits. A fire salamander at La Quinetière, Buais, Normandy. Credit: wwarby/Flickr, CC BY 2.0

A series of biochemical reactions at play when a salamander regrows its limbs have been identified to help catalyse the healing of broken bones – but within some important limits. A fire salamander at La Quinetière, Buais, Normandy. Credit: wwarby/Flickr, CC BY 2.0

On the night of September 15, 2015, when Luke Shaw, the left-back at Manchester United, was brought down by a heavy challenge, little did anyone guess that the man wouldn’t participate in the game not only that night but for months. And he may have been luckier, too – players like Luc Nilis (Aston Villa), Alf Inge Haaland (Manchester City) and David Busst (Coventry) were forced to retire from the game due to injuries they never fully recovered from. While sports injuries such as these are highly debated, a true fan of the game only hopes for quick recoveries of the player and seeing him on the pitch again.

But in case of a fracture, such as in Shaw’s, quick recovery means faster healing of the bone and that‘s something we’ve acquired little control over. Modern medicine has always dealt with bone fractures in an archaic way. A patient with a fracture is given all the help when it comes to dealing with the pain associated with the break but there’s little assistance available when it comes to healing the bone itself. Bone-healing is allowed to progress naturally, with no drug that we know of that can actually accelerate the process – but this could change soon. In a recent study published in the journal Stem Cells, researchers have been able to show that carefully stimulating a select cascade of biochemical changes in the body can set the stage for faster fracture healing.

The cascade – called the canonical Wnt pathway – is important in embryonic development, which includes the formation of bones and muscles, and tissue regeneration in the adult bone marrow. While the Wnt pathway was primarily noted for its role in cancer, it’s now caught the attention of many as the reason why salamanders can regrow limbs. Although regrowing limbs might seem like science fiction for humans (for now), the Wnt pathway is constantly working during the process of growth as well as maintenance of the body and is therefore important during the process of healing as well.

Previous studies (this and this) have identified that mutations in the genes that make up the Wnt pathway result in significant changes in bone densities. So mutation in one of the genes might lead to rapid loss of bone mass while another might increase bone mass to levels higher than normal. This is why the Wnt pathway has also been a target for potential drugs – like romosozumab – for treatment of osteoporosis.

However, fracture-healing is not unidirectional like bone disease. In osteoporosis, the bone is weakened in a continuous process that needs to be arrested or, better still, reversed. Fracture-healing on the other hand goes through multiple phases, each needing a specific stimulus. And as other research has shown, prolonged activation of the Wnt pathway actually reverses bone-healing. As a result, there’s a compelling need to identify the window of opportunity within which the Wnt pathway can be triggered to bring about faster bone healing, not anything else.

Using bone marrow mononuclear cells, the researchers who published in Stem Cells – from the Centre for Human Development, Stem Cells and Regeneration, University of Southampton – found that stimulating the Wnt pathway during the early stages of healing results in the connective tissue cells of an organ being recruited to form new bone fragment. And overdoing just this is what, after a point, stalls bone formation.

Dr. Nick Evans, the principal investigator for the study, points out that treating bone marrow cells in the lab is very different treating them in the body. When contacted over email, he said, “We did not show any effect in vivo but only worked in vitro (post isolation). It is important that we can demonstrate these sorts of effects in fracture healing models.”

So, any drug developed as a result of the study wouldn’t be very useful if it failed to target bone marrow cells at the site of the fracture. Be that as it may, another recent development drastically improves our ability to target cells in the bone. Researchers at Harvard Medical School were able to deliver an approved cancer drug to metastatic bone lesions using nanoparticles. Since fracture sites are characterised by high inflammation, similar nanoparticles could be developed to zero in on the sites of these inflammations.

“We are currently interested in how we might deliver drugs at the right time and place,” Dr. Evans said, but wouldn’t discuss the idea further as the results await publication. Although his lab isn’t working on any specific drug at the moment, it has an eye on this area of research.

Nonetheless, finding the incentives to and limitations on working the Wnt pathway itself will hike hopes of achieving a targeted and quicker healing of fractures. And it’s not just the accidental fractures that can be healed faster: osteoporosis-related fractures among the elderly, which heal slowly or not at all have, huge financial impacts on healthcare and also reduce the quality of life. Further research in this area is likely to have positive outcomes for them in the future.

Ameya Paleja is a molecular biologist based in Hyderabad and blogs at Coffee Table Science.