Proteomic characterization of a trauma-based rat model of heterotopic ossification identifies interactive signaling networks as potential therapeutic targets

Abstract

Heterotopic ossification (HO) is the formation of ectopic bone in soft tissues observed in patients following blast injuries, orthopedic or head trauma, burns, or in the context of inborn mutations of genes involved in osteogenesis. There is no universally accepted therapy for HO. This study has used global unbiased mass spectrometry proteomic approaches, validated by western immunoblots, to interrogate skeletal muscle tissues obtained from a highly reproducible rat model of trauma induced HO. During early the phase of HO development, statistically significant modulation of proteins within the following pathways was identified: coagulation, cyclic AMP, extracellular matrix, immunity/inflammation, NADH metabolism, TGFβ. These metabolic proteins and pathways have the potential to serve as diagnostic, prognostic, and therapeutic targets for this devastating orthopedic condition that has considerable impact on the patient's quality of life. Furthermore, the findings confirm and extend previous in vitro stromal/stem cell and clinical studies from the field. SIGNIFICANCE: This study confirms and extends the field's understanding of the protein pathways that are modulated in a rat model of trauma induced heterotopic ossification. The identification of specific proteins such as the AP1 transcription factor as well as protein families such as the complement/coagulation pathway and serine protease inhibitors as biomarkers have potential clinical translational value. These outcomes have relevance to the physiological and pathological mineralization processes contributing to the recovery of orthopedic trauma patients.