Osteogenic gene expression correlates with development of heterotopic ossification in war wounds

Clin Orthop Relat Res. 2014 Feb;472(2):396-404. doi: 10.1007/s11999-013-3325-8. Epub 2013 Oct 18.


Background: Heterotopic ossification (HO) is a frequent complication of modern wartime extremity injuries. The biological mechanisms responsible for the development of HO in traumatic wounds remain elusive.

Question/purposes: The aims of our study were to (1) characterize the expression profile of osteogenesis-related gene transcripts in traumatic war wounds in which HO developed; and (2) determine whether expression at the mRNA level correlated with functional protein expression and HO formation.

Methods: Biopsy specimens from 54 high-energy penetrating extremity wounds obtained at the initial and final surgical débridements were evaluated. The levels of selected osteogenic-related gene transcripts from RNA extracts were assessed by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. As a result of its key role in osteogenesis, the concentration of BMP-2 in the effluent of 29 wounds also was determined.

Results: The transcripts of 13 genes (ALPL [p = 0.006], BMP-2 [p < 0.001], BMP-3 [p = 0.06], COL2A1 [p < 0.001], COLL10A1 [p < 0.001], COL11A1 [p = 0.006], COMP [p = 0.02], CSF2 [p = 0.003], CSF3 [p = 0.012], MMP8 [p < 0.001], MMP9 [p = 0.014], SMAD1 [p = 0.024], and VEGFA [p = 0.017]) were upregulated greater than twofold in wounds in which HO developed compared with wounds in which it did not develop. Gene transcript expression of BMP-2 also correlated directly with functional protein expression in the wounds that formed HO (p = 0.029).

Conclusions: Important differences exist in the osteogenic gene expression profile of wounds in which HO developed compared with wounds in which it did not develop. The upregulation of multiple osteogenesis-related gene transcripts indicates the presence of a proosteogenic environment necessary for ectopic bone formation in traumatic wounds.

Clinical relevance: Understanding the osteogenic environment associated with war wounds may allow for the development of novel therapeutic strategies for HO.

MeSH terms

  • Adolescent
  • Adult
  • Afghan Campaign 2001-*
  • Biopsy
  • Bone Morphogenetic Protein 2 / analysis
  • Bone Morphogenetic Protein 2 / genetics
  • Gene Expression Profiling / methods
  • Gene Expression Regulation
  • Genetic Markers
  • Humans
  • Iraq War, 2003-2011*
  • Male
  • Military Medicine*
  • Military Personnel
  • Ossification, Heterotopic / genetics*
  • Ossification, Heterotopic / metabolism
  • Ossification, Heterotopic / prevention & control
  • Osteogenesis / genetics*
  • Prognosis
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Up-Regulation
  • Wounds, Penetrating / complications
  • Wounds, Penetrating / genetics*
  • Wounds, Penetrating / metabolism
  • Wounds, Penetrating / therapy
  • Young Adult


  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • Genetic Markers
  • RNA, Messenger