Discovery of New Treatments and Biomarkers for Neurogenic Heterotopic Ossifications Following Spinal Cord Injuries
Abstract
A frequent complication of spinal cord injuries is the formation of bones in soft tissues outside of the skeleton. These misformed bones usually grow around joints such as the knee, hip, elbow, or shoulder and are called “neurogenic heterotopic ossifications (NHOs).” They occur in up to 20%-29% of civilians suffering spinal cord injuries and are extremely prevalent in Soldiers who are victims of battlefield injuries affecting the spinal cord or brain, with these bones developing in up to 60% of cases. These misformed bones start to develop a few weeks after the spinal cord injury, with the first signs of this condition being detected as inflammatory pain. These bones then develop over a few months to become so large (up to 2 kg) that patients can no longer bend their joints, as their joints are encased in bone. Heterotopic ossification is an extremely debilitating condition which impacts not only the well-being and rehabilitation of patients living with spinal cord injury, but also their caregivers. The loss of flexibility in the joints creates a variety of challenges in routine daily tasks such as sitting upright in a wheelchair, as well as eating and dressing independently. In addition, these bones can entrap large blood vessels and nerves, which contributes to increasing pain and paralysis. We have known about the formation of these heterotopic bones for over 100 years, as they were first observed in Soldiers with spinal cord injuries when the first X-ray machines were used during World War I. Since then, little progress has been made in understanding why these abnormal bones develop, and due to this lack of understanding, there is still no effective treatment to prevent or stop the formation of these bones. Currently, the only treatment is surgical removal once these misformed bones have become so large that they further disable the patient. These are long and complicated operations performed under general anesthesia, as the patients are already fragile due to the spinal cord injury, and removing these large ossifications around joints without damaging the joint, large blood vessels, and nerves they entrap is very challenging, with a high risk of bleeding. Yet, even after these heterotopic bones have been removed, they can still grow back, and another surgery is required to remove them again. To understand why these misformed bones grow, we have developed a pre-clinical animal model that replicates the complications of heterotopic ossifications after spinal cord injuries in patients. As we are the first scientists to have successfully developed a pre-clinical model of NHO after spinal cord injury, we are leaders in this field. Using this model, we have discovered that the spinal cord injury alone is not sufficient to cause NHO, as these bones only develop if there is also concomitant muscle damage. We have also discovered that NHO are driven by a type of white blood cell that is involved in mounting an immune response to tissue damage and infections. These cells, called “macrophages,” produce an abnormal range of molecules in response to muscle damage and spinal cord injury, which stimulate the formation of heterotopic bones instead of muscle repair. We now have results from our previous research projects suggesting that a stress response from the spinal cord injury leads to the release of a stress hormone into the blood which directly promotes NHO development. In addition, macrophage proteins driving inflammation and molecules produced by microbes (bacteria and fungi) during infections exacerbate NHO development. This is in good agreement with what doctors observe, as spinal cord injury patients with additional infections (urinary tract, pneumonia, systemic infections) or inflammation (bedsores, smokers) are much more likely to develop NHO. In this study, we aim to understand how this stress response, excessive inflammation, and infectious microbes combine to enhance NHO, and determine whether combining medicines
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110560
Entities
People
- Jean-Pierre Lévesque
Organizations
- United States Army
- University of Queensland