In vivo model of human post-traumatic heterotopic ossification demonstrates early fibroproliferative signature

Abstract

Background The relationship between the tissue injury healing response and development of heterotopic ossification (HO) is poorly understood. Here we compare a rat blast model and human traumatized muscle from a blast injury to study the early signatures of osteogenesis and fibrosis during the formation of HO. Methods Rat and human tissues were characterized using histology, scanning electron microscopy, immunohistochemistry, as well as gene and protein expression analysis. Additionally, animals and humans were assessed radiographically for HO formation following injury. Results Markers of bone formation were dramatically increased in tissue samples from both humans and rats, and both displayed increased fibroproliferative regions within the injured tissues and elevated expression of markers of tissue fibrosis such as TGF-β1, Fibronectin, SMAD3 and PAI-1. Markers of inflammation and fibrosis ( ACTA , TNFα , BMP1 and BMP3 ) were elevated at the RNA level in both rat and human samples. By day 42, bone formation in the rat blast model appeared similar in radiographs compared to human patients who progressed to develop post-traumatic HO. Conclusions Our data demonstrates that a similar early fibrotic response is evident in both the rat blast model and the human tissues following a traumatic injury and demonstrates the relevance of this animal model for future translational studies.

Association Between Ionized Calcium Concentrations During Hemostatic Transfusion and Calcium Treatment With Mortality in Major Trauma

“…However, severe consequences of calcium administration have also been reported, such as cardiac cellular apoptosis and the precipitation of calcium salts. 31 Achieving the right balance requires further study to avoid complications of undertreatment or overtreatment of hypocalcemia in trauma.…”

The development of a mouse model to investigate the formation of heterotopic ossification

“…The researchers from Pellegrini's lab established the HO rat model following blast Am procedure, and found that HO demonstrated early fibroproliferative signature. 17,18 In addition, the study from Forsberg and Potter's lab confirmed that the serum from HO patients could activate mitogen activated protein kinase signaling in adipose stem cells. 19 The authors from Levi and Davis's Lab found that BMP signaling made great contribution to osteogenic differentiation as well as ectopic bone formation and blocking BMP signaling may be an effective prophylactic strategy for HO following blast-related lower extremity trauma.…”

Genetic heterogeneity of heritable ectopic mineralization disorders in a large international cohort

“…The NGS panel contained 21 ectopic mineralization-associated genes (ABCC6, ADIPOQ, AHSG, ANKH, APOE, ATF4, CASR, ENPP1, FAM20A, FGF23, GALNT3, GGCX, KL, MGP, NT5E, SAMD9, SLC20A2, SLC29A1, SPP1, TRIM24, and TNFRSF11B) 8 and 8 genes (A2AP, ALPL, ENTPD1, PAI-1, PLAT, PLAU, PLAUR, and PLG) involved in the fibrinolysis pathway and regulation of ectopic mineralization in soft tissue after injury. [9][10][11][12] We performed variant detection and bioinformatic analyses according to previously published approaches. 13,14 Final prioritization of variants employs a 2-tiered procedure following the latest American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) 15 and Sherloc guidelines.…”