Abstract
Following severe trauma, fracture healing is impaired because of overwhelming systemic and local inflammation. Glucocorticoids (GCs), acting via the glucocorticoid receptor (GR), influence fracture healing by modulating the trauma-induced immune response. GR dimerization-dependent gene regulation is essential for the anti-inflammatory effects of GCs. Therefore, we investigated in a murine trauma model of combined femur fracture and thoracic trauma, whether effective GR dimerization influences the pathomechanisms of trauma-induced compromised fracture healing. To this end, we used mice with decreased GR dimerization ability (GRdim). The healing process was analyzed by cytokine/chemokine multiplex analysis, flow cytometry, gene-expression analysis, histomorphometry, micro-computed tomography, and biomechanical testing. GRdim mice did not display a systemic or local hyper-inflammation upon combined fracture and thorax trauma. Strikingly, we discovered that GRdim mice were protected from fracture healing impairment induced by the additional thorax trauma. Collectively and in contrast to previous studies describing the beneficial effects of intact GR dimerization in inflammatory models, we report here an adverse role of intact GR dimerization in trauma-induced compromised fracture healing.
Highlights
Fracture healing is largely impaired in patients suffering from multiple injuries [1, 2]
Twenty-four hours following isolated fracture (Fx) or combined fracture and thoracic trauma (Fx+TxT), we found that the chemokines CXCL-1, IL-6, and monocyte chemotactic protein (MCP)-1 in plasma had increased by trend in wild type mice receiving additional thoracic trauma to the initial fracture compared to the wild type mice that had fracture alone (Figures 2A–C)
The present study investigated the role of endogenous GC signaling through the dimeric glucocorticoid receptor (GR) during both, isolated and compromised fracture healing induced by an additional thoracic trauma
Summary
Fracture healing is largely impaired in patients suffering from multiple injuries [1, 2]. Thoracic trauma represents a critical injury in multi-injured patients and it frequently occurs in association with fractures. Thoracic trauma is a strong inducer of the posttraumatic systemic inflammation. Thoracic trauma can lead to acute lung injury, a strong inflammatory response in the lungs, which affects a subfraction of patients, leading to a systemic trigger that impacts on the whole organism [7]. Endogenous glucocorticoids (GCs) are stress hormones that play a crucial role in controlling inflammation and maintaining bone mass [10, 11]. We previously demonstrated that endogenous GCs signaling through the glucocorticoid receptor (GR) is critical for efficient fracture healing [12]. Less is known about the function of GCs during bone regeneration in the context of multiple injuries
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