Bone healing following trauma is known to be associated with an early increase in serum concentrations of several pro-inflammatory and angiogenic growth factors. However, the temporal pattern of growth factors (GFs) involved in bone formation and their relationship with trauma severity has not been explored. Furthermore, to what extent osteogenic progenitors, including mesenchymal stem cells (MSCs) are ‘mobilized’ following trauma is unknown.
This study investigated the systemic levels of four GFs (PDGF-AA, TGF-β2, follistatin and angiogenin) over the first two weeks following trauma in three groups of patients with increasing severity (Isolated trauma (n=15), Polytrauma (n=15), and Head injury (n=14)) and compared to Healthy Controls (n=9). The dynamics of GF release measured by ELISA was correlated with clinical and biochemical inflammatory parameters and the healing outcome assessed by clinical and radiological parameters as well as requirement of surgical re-interventions. Potential MSC mobilization from their iliac crest bone marrow (ICBMA) niches into peripheral circulation was measured by standard colony-forming assay-fibroblast, at least twice following trauma. Further correlations were sought with circulating levels of platelets, PDFG-BB and PDGF-AA.
Growth factors described as anabolic for bone (PDGF-AA and angiogenin) had an initial suppression following trauma (50% and 80% by day 1, respectively), whereas inhibitory GF follistatin was upregulated compared to control (1.5-fold by day 1). This effect was more pronounced with increasing trauma severity. The variability of TGF-β2 was too high to allow differences between trauma groups to be detected. The dynamics of all GFs were not correlated with the inflammatory state of the patients, assessed both clinically (Systemic Inflammatory Response Syndrome score) and biochemically (total white cell count, C-reactive protein and platelet levels). However, there was a significant correlation between levels of time-matched PDGF-AA and platelets (p<0.01, r=+0.61), independent of trauma severity. A marked suppression of TGF-β2 throughout the time course which reached statistical significance in the first week following trauma (5-fold, p<0.05) was observed in patients identified as ‘poor healers’; the same group additionally displayed an altered dynamics of follistatin release compared to patients who healed normally.
The numbers of ICBMA MSCs were dynamic over time in the same patient, but did not correlate with trauma severity or patients’ inflammatory state. Instead, significant correlations were observed between the changes in ICBMA MSC numbers and changes the levels of PDGF-AA (p<0.01, r=+0.55), and PDGF-BB (p=0.03, r=+0.38) and circulating platelets (p=0.02, r=+0.44). No MSCs were found in patients’ peripheral blood at any time point studied.
These data indicated that measuring GFs implicated in BMP signalling pathway may lead to the discovery of novel biomarkers of fracture non union. Measuring patient’s inflammatory response following fracture did not correlate with the release of growth factors studied suggesting that these phenomena were independent. Limited MSC mobilization in the bone marrow (but not into PB) did take place but appeared to be related to platelet counts and a possible release of PDGF-AA and PDGF-BB GFs, which are known to be mitogenic for MSCs. It was not linked to trauma severity or predictive of the healing outcome. Further research is needed to investigate the predictive value of TGF-β2 and follistatin in a larger cohort of patients. Whilst this is the first study showing a ‘dynamic’ nature of the MSC pool in human BM, further work should determine whether the influence of platelets is due to enhanced MSC migration or their proliferation in situ.
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