Neurogenic Heterotopic Ossification (NHO) is a very incapacitating condition where ectopic bones form in skeletal muscles and joints of individuals who suffer spinal cord injury (SCI) and traumatic brain injury (TBI). The pathophysiology isn’t still completely understood. As a result, clinicians are left with limited therapies and no prophylactic management. Due to this unmet clinical need, we aim to understand the mechanisms involved and identify the causative and exacerbating factors of NHO.
To elucidate NHO pathogenesis, we developed the first murine model of SCI-NHO, in which NHO is induced via a combination of cardiotoxin induced muscle injury and a SCI. Using this model, we recently established that fibroadipoprogenitors (FAP) are the locally derived cells-of-origin in muscles developing NHO.
Recent retrospective studies in SCI and TBI patients show that the presence of local or systemic infections is a significant risk factor of developing NHO. Pathogen Associated Molecular Patterns (PAMPs) are molecular structures found in microbes, which are recognised by our innate immune system via Pattern Recognition Receptors (PRRs). To investigate whether PAMPs exacerbate NHO directly via FAPs, we established in vitro osteogenic cultures of FAPs supplemented with purified synthetic and natural PAMPs from bacteria, fungi and virus.
After two weeks of osteogenic culture, we observed that PAMPs such as Pam2CSK4 which activates TLR2/TLR6 dimers, Pam3CSK4 which activates TLR1/TLR2 dimers and Zymosan which activates Dectin 1, Dectin 2 and TLR2/TLR6 dimers induced a dose-dependent increase in mineralisation. These studies suggest that PAMPs have the potential to exacerbate FAP mineralisation in vitro but further studies are needed to confirm a similar response in vivo.