'Sonic the Hedgehog' gene could speed to the rescue of major bone repair

From Sega to skeletons—Sonic the Hedgehog may have found a new use. But rather than the speedy blue creature beloved of computer gamers, this sonic is a gene that could play a vital role in repairing major bone injuries.

Like humans, mice are able to regrow large sections of missing rib. By observing how mice recovered from the surgical resection of a 3-mm segment of rib bone, Maxwell Serowoky, a Ph.D. student in the USC Stem Cell laboratory of Francesca Mariani, Ph.D., and his colleagues noticed an increase in the activity of a protein dubbed "Sonic Hedgehog," which is encoded by the SHH gene. The gene had already been identified as playing an important role in skeletal formation in embryos but hadn’t yet been linked to injury repair in adults.

In their findings, published May 17 in the journal NPJ Regenerative Medicine, the researchers showed that activity of the sonic hedgehog protein increased for a brief period after a significant rib injury but had returned to normal levels within five days. This was enough time to ensure the creation of a callus, which is the initial scaffold that connects across a fractured bone. Genetically modified mice without the SHH gene were unable to form a callus and therefore couldn’t heal their ribs, the researchers noted.

Their research also threw up another surprise: SHH did not originate from specific progenitor cells in the periosteum that are known to be essential for healing large injuries. Instead, it originates from stem-cell-like cells called mesenchymal cells.

The findings offer huge potential for human treatment. “Our discovery may inform future therapeutic strategies for situations where patients are missing large sections of bone following high energy injuries such as traffic accidents or combat wounds, or after cancer-related bone resections,” said the study's co-author Jay Lieberman, M.D., chair and professor of orthopedic surgery at the Keck School of Medicine of USC.

The hedgehog (HH) gene was first discovered in a type of fruit fly as part of the Nobel Prize-winning work of Christiane Nüsslein-Volhard and Eric Weischaus. While these flies have a single hedgehog gene, mammals have three versions: sonic hedgehog (SHH), Indian hedgehog (IHH) and desert hedgehog (DHH).

It may have the most recognizable name, but sonic is not the first time gene therapies have been investigated as a potential bone repair therapy. A Cedars-Sinai-led team discussed its work on a combination treatment of ultrasound, stem cells and gene therapy back in 2017. Repairing bones has also been touted as one of the myriad potential uses of mRNA beyond COVID-19 vaccines.