Findings open way to treat debilitating spinal injury complication

A Mater Research team based at the Translational Research Institute (TRI), are unravelling the causes of a painful and incapacitating complication affecting 1 in 5 people following a traumatic brain or spinal cord injury.

TRI-based Mater Research Principal Fellow, Professor Jean-Pierre Levesque and his group are world-leaders in neurogenic heterotopic ossifications (NHOs) research. 

Professor Levesque said NHOs can form in people with spinal injuries, especially soldiers, when something goes horribly wrong with the body’s ability to repair damaged skeletal muscle tissue.

“Their body starts producing bones around their joints where there would normally be soft tissue, which as you can imagine is incredibly painful and incapacitating for the person because the affected joints can no longer move,” he said.

Until now, very little has been understood about the processes leading to NHOs, but using a unique laboratory model, the Levesque Group and their French collaborators have made several new discoveries.

While the research group has previously shown that the condition only develops when there is an injury of the central nervous system combined with muscular trauma, they have now discovered how NHOs develop in people with these injuries.

Professor Levesque said they had shown that not only do NHOs begin developing very quickly, within days of the neurological injury, but that they are the result of a complex cascade process that creates an abnormal bone forming environment in injured skeletal muscles.

“Through our work, we’ve been able to identify some of the key signalling processes leading to NHOs, and to better understand the role of the immune system and stress hormones in triggering the process,” said Professor Levesque.

“Importantly, we’ve also been able to identify cells within injured muscles which are reprogrammed to produce bone instead of undergoing programmed cell suicide, a process necessary for normal muscle repair.

“These findings will help us develop new therapeutic strategies to prevent or treat neuro-musculoskeletal complications in spinal cord injury patients.”

TRI’s Preclinical Imaging services played a small, but significant role in the Levesque Group’s research, providing specialised microCT imaging, training and support with developing the workflow for data analysis.

The research was funded by the National Health and Medical Research Council and the US Department of Defence.

The findings outlined in this story were reported in the following publications:

• Debaud C., Tseng H.W., Chedik M., Kulina I., Genêt F., Ruitenberg M.J., Levesque J.P., “Local and Systemic Factors Drive Ectopic Osteogenesis in Regenerating Muscles of Spinal-Cord-Injured Mice in a Lesion-Level-Dependent Manner”. J Neurotrauma, 2021 Aug 1;38(15):2162-2175. doi: 10.1089/neu.2021.0058.

• Alexander, K. A., Tseng, H. W., Kulina, I., Fleming, W., Vaquette, C., Genêt, F., Ruitenberg, M. J., & Lévesque, J. P., “Lymphocytes Are Not Required for Neurogenic Heterotopic Ossification Development after Spinal Cord Injury”. Neurotrauma reports, 2022; 3(1): 87–96. doi: 10.1089/neur.2021.0072

• Tseng HW, Girard D, Alexander KA, Millard SM, Torossian F, Anginot A, Fleming W, Gueguen J, Goriot ME, Clay D, Jose B, Nowlan B, Pettit AR, Salga M, Genêt F, Bousse-Kerdilès ML, Banzet S, Lévesque JP., “Spinal cord injury reprograms muscle fibroadipogenic progenitors to form heterotopic bones within muscles”, Bone Res., 2022;10(1):22. doi: 10.1038/s41413-022-00188-y.

• Tseng HW, Kulina I, Girard D, Gueguen J, Vaquette C, Salga M, Fleming W, Jose B, Millard SM, Pettit AR, Schroder K, Thomas G, Wheeler L, Genêt F, Banzet S, Alexander KA, Lévesque JP., “Interleukin-1 Is Overexpressed in Injured Muscles Following Spinal Cord Injury and Promotes Neurogenic Heterotopic Ossification”, J Bone Miner Res, 2022 Mar;37(3):531-546. doi: 10.1002/jbmr.4482