Temporal Pattern of Gene Expression and Histology of Stress Fracture Healing
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Loading of the rat ulna is an ideal model to examine stress fracture healing. The aim of this study was to undertake a detailed examination of the histology, histomorphometry and gene expression of the healing and remodelling process initiated by fatigue-loading of the rat ulna. Ulnae were harvested 1, 2, 4, 6, 8 and 10 weeks following creation of a stress fracture. Fracture healing involved direct remodelling that progressed along the fracture line as well as woven bone proliferation at the site of the fracture. Histomorphometry demonstrated rapid progression of basic multicellular units from 1-4 weeks with significant slowing down of healing by 10 weeks after loading. Quantitative PCR was performed at 4 hours, 24 hours, 4 days, 7 days and 14 days after loading. Gene expression was compared to an unloaded control group. At 4 hours after fracture there was a marked, 220-fold increase (P<0.0001) in expression of IL-6. There were also prominent peak increases in mRNA expression for OPG, COX-2, and VEGF (all P<0.0001). At 24 hours there was a peak increase in mRNA expression for IL-11 (73-fold increase, P<0.0001). At 4 days there was a significant increase in mRNA expression for Bcl-2, COX-1, IGF-1, OPN, and SDF-1. At 7 days there was significantly increased mRNA expression of RANKL and OPN. Prominent, up-regulation of COX-2, VEGF, OPG, SDF-1, BMP-2 and SOST prior to peak expression of RANK-L indicates the importance of these factors in mediating directed remodelling of the fracture line. Dramatic, early up-regulation of IL-6 and IL-11 demonstrate their central role in initiating signalling events for remodelling and stress fracture healing.
© 2010 Elsevier. This is the author-manuscript version of this paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.