High energy open fractures are prone to delayed and non-union, necessitating secondary
reconstruction or amputation and are associated with prolonged pain, disability and loss of
income. Current strategies for accelerating healing require the addition of high
concentrations of bone morphogenetic proteins or ex vivo expansion and/or viral
transduction of autologous, marrow-derived stem cells for re-implantation. It is established
that prompt cover with vascularised tissue is required to prevent bony infection. Coverage
with muscle improves healing time and union strength in an experimental model but the
reason for this finding remains unclear.
The fracture environment, simulated by supernatant produced using human fractured bone
fragments was found to promote the migration and osteogenic differentiation of human
skeletal muscle derived cells (MDSC). These cells displayed a mesenchymal stromal
phenotype. TNF-α and IL-6 promoted osteogenic differentiation of MDSC. TNF-α and IL-6
also promoted the migration of MDSC in vitro but did not appear to influence their
proliferation. Using an in vivo periosteally stripped (high energy) fracture model, the P55
(TNF receptor-1) knockout exhibited early delay. Recombinant TNF-α promoted fracture
healing in wild type mice but was inhibitory at high concentrations. The peri-fracture
inflammatory infiltrate was comprised mainly of neutrophils. T cells were also present.
Severe, combined immunodeficient mice exhibited delayed fracture healing.
The study establishes the role of muscle derived stromal cells as an osteoprogenitor
population, which may be important in healing high-energy fractures stripped of
periosteum. These cells migrate and differentiate down an osteogenic lineage in response
to TNF-α, present in the fracture environment. Fracture healing is critically dependent on
TNF-α concentration locally and a high local concentration may be inhibitory. Fracture
healing may be promoted by manipulating inflammation locally. Neutrophils and T cells are
both potential sources of TNF-α.