Abstract
Heterotopic ossification (HO) refers to the abnormal formation of bone in soft tissue. Although some of the underlying processes of HO have been described, there are currently no clinical tests using validated biomarkers for predicting HO formation. As such, the diagnosis is made radiographically after HO has formed. To identify potential and novel biomarkers for HO, we used isobaric tags for relative and absolute quantitation (iTRAQ) and high-throughput antibody arrays to produce a semi-quantitative proteomics survey of serum and tissue from subjects with (HO+) and without (HO−) heterotopic ossification. The resulting data were then analyzed using a systems biology approach. We found that serum samples from subjects experiencing traumatic injuries with resulting HO have a different proteomic expression profile compared to those from the matched controls. Subsequent quantitative ELISA identified five blood serum proteins that were differentially regulated between the HO+ and HO− groups. Compared to HO− samples, the amount of insulin-like growth factor I (IGF1) was up-regulated in HO+ samples, whereas a lower amount of osteopontin (OPN), myeloperoxidase (MPO), runt-related transcription factor 2 (RUNX2), and growth differentiation factor 2 or bone morphogenetic protein 9 (BMP-9) was found in HO+ samples (Welch two sample t-test; P < 0.05). These proteins, in combination with potential serum biomarkers previously reported, are key candidates for a serum diagnostic panel that may enable early detection of HO prior to radiographic and clinical manifestations.
Highlights
Heterotopic ossification (HO), the abnormal formation of mature lamellar bone in nonosseous tissue, is a significant problem for wounded soldiers that have survived high energy blast injuries [1,2]
HO occurs post-trauma in elective hip arthroplasty, externally fixed distal humerus fractures (42%), spinal cord injury (SCI), and closed brain injury in civilian populations [4]
The HOÀ tissue samples were acquired mainly through total hip arthroplasty, whereas the HO+ samples were acquired via hip revision or HO excision (Table 1)
Summary
Heterotopic ossification (HO), the abnormal formation of mature lamellar bone in nonosseous (soft) tissue, is a significant problem for wounded soldiers that have survived high energy blast injuries [1,2]. A recent study on soldiers from Operation Enduring Freedom and Operation Iraqi Freedom reveals that the highest risk of HO follows amputation from a blast mechanical injury, with HO accounting for >60% combat-related extremity injuries [1,3]. In the military population, formation of HO is associated with chronic pain, prostheses not fitting properly, joint ankylosis, functionality limitations, longer rehabilitation, and substantial morbidity [3]. Non-steroidal anti-inflammatory (NSAID) drugs and radiation therapy used prophylactically can be effective as a treatment for HO, many patients need at least one surgical excision of ectopic bone [5]. Multiple diagnoses, including hemostasis and polytrauma, often present in combat casualties, make these prophylactic treatments contraindicated, and currently there are no pharmaceutical treatments yet approved by the United States Federal Drug Administration to treat HO once present [5]
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