Abstract
Heterotopic ossification (HO) is a debilitating condition defined by the rapid formation of bone in soft tissues. What makes HO fascinating is first the rate at which bone is deposited, and second the fact that this bone is structurally and compositionally similar to that of a healthy adult. If the mechanisms governing HO are understood, they have the potential to be exploited for the development of potent osteoinductive therapies. With this aim, a tissue‐engineered skeletal muscle was used model to better understand the role of inflammation on this debilitating phenomenon. It was shown that myoblasts could be divided into two distinct populations: myogenic cells and undifferentiated ‘reserve’ cells. Gene expression analysis of myogenic and osteoregulatory markers confirmed that ‘reserve’ cells were primed for osteogenic differentiation but had a reduced capacity for myogenesis. Osteogenic differentiation was significantly enhanced in the presence of platelet‐derived growth factor (PDGF)‐BB and bone morphogenetic protein 2 (BMP2), and correlated with conversion to a Sca‐1+/CD73+ phenotype. Alizarin red staining showed that PDGF‐BB promoted significantly more mineral deposition than BMP2. Finally, it was shown that PDGF‐induced mineralization was blocked in the presence of the pro‐inflammatory cytokines tumour necrosis factor‐α and interleukin 1. In conclusion, the present study identified that PDGF‐BB is a potent osteoinductive factor in a model of tissue‐engineered skeletal muscle, and that the osteogenic capacity of this protein was modulated in the presence of pro‐inflammatory cytokines. These findings reveal a possible mechanism by which HO develops following trauma. Importantly, these findings have implications for the induction and control of bone formation for regenerative medicine. © 2016 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons Ltd.
Highlights
Heterotopic ossification (HO) is a debilitating condition defined by the de novo formation of bone within nonosseous soft tissues
The C2C12 myoblasts cultured in tissue engineered collagen gels could be separated into distinct myogenic and non-myogenic ‘reserve’ cell populations
We demonstrate that exposure to platelet-derived growth factor (PDGF)-BB promoted significantly more mineral deposition and expression of key osteogenic markers in ‘reserve’ cell cultures than bone morphogenetic protein 2 (BMP2), the current gold-standard osteoinductive factor in animal studies of HO
Summary
Heterotopic ossification (HO) is a debilitating condition defined by the de novo formation of bone within nonosseous soft tissues. The formation of bone at atypical sites can have serious consequences such as neurovascular entrapment, and has a significant impact on an individual’s quality of life (Colachis et al, 2004). Acquired HO is associated with severe trauma that can result as a consequence of injuries, burns or changes in local biomechanics following reparative surgeries (Davies et al, 2015). Previous studies have identified an association between inflammatory cytokine and chemokine expression and heterotopic ossification (Evans et al, 2012), and it has been suggested that certain combinations of these proteins may be used to predict the onset of HO (Forsberg et al, 2014). At present, the exact relationship between post-trauma inflammation and HO remains unknown
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