Artikel
Mast cells contribute to compromised bone regeneration after trauma
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Autoren
Veröffentlicht: | 25. Oktober 2022 |
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Gliederung
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Objectives: Mast cells (MCs) contribute to the inflammatory response induced by hemorrhagic shock, severe tissue injury or sepsis. They are highly responsive to alarm signals generated after trauma, and release many inflammatory mediators including IL-6, a key mediator of posttraumatic inflammation. An overwhelming systemic inflammation is the main reason for compromised bone healing after severe trauma, however, underlying cellular and molecular mechanisms are poorly understood. Recently, we found that bone resident MCs trigger local and systemic inflammatory responses after isolated fracture. Thus, we here investigated if MCs contribute to trauma-induced compromised bone healing.
Methods: Male MC-deficient Mcpt5-Cre+ R-DTA mice (12-weeks-old), which lack connective tissue MCs, and their MC-competent Cre- littermates underwent isolated femur osteotomy or combined with an additional thoracic trauma. Posttraumatic inflammation and bone repair were assessed 3h and 21d after injury, respectively. Inflammatory mediators were analyzed in the serum and bronchoalveolar lavage (BAL) fluid. The fracture callus was assessed by biomechanical testing, micro-computed tomography, histomorphometry and immunohistochemistry (n=3-8/group, Student's t-test, ANOVA/Dunn's posthoc, p<0.05).
Results and conclusion: In MC-competent mice, the inflammatory response 3h after combined trauma was significantly increased compared to isolated fracture shown by increased serum levels of the inflammatory mediators IL-6 (40 vs 151 pg/ml), IL-5 (0 vs 6.5 pg/ml), CXCL10 (1.1 vs 8.2 pg/ml) and Mcp3 (60 vs 109 pg/ml). Notably, MC-deficient mice did not show an increased inflammatory response after combined trauma. Moreover, serum IL-6 (-67%, p=0.014) and CXCL10 (-48%, p=0.027) levels were reduced compared to MC-competent mice after thoracic trauma, suggesting that connective tissue MCs trigger the posttraumatic inflammation after trauma. In contrast, in the BAL both MC-competent and -deficient mice had increased levels of inflammatory mediators including IL-6 or Mcp3 after combined trauma, which could be explained by the fact that lungs of Mcpt5-Cre R-DTA mice still contain mucosal MCs. On d21 after fracture, bone repair was compromised in MC-competent mice after combined trauma shown by a reduced bone content (-27%, p=0.046) of the fracture callus and persisting cartilage (+332%, p=0.022) at the fracture gap compared to isolated fracture. In addition, more MCs (2.6 vs 6.8/mm2, p=0.031) were present locally in the fracture callus of MC-competent mice after thoracic trauma. Notably, in MC-deficient mice bone healing was not compromised after combined trauma at day 21.
Our results show that MC-deficient mice display a reduced acute inflammatory response and uneventful bone repair after severe trauma. Thus, we can confirm that MCs might critically contribute to trauma-induced compromised bone healing. Our study implies that MCs could be a target for new therapeutic strategies to improve bone repair in multiple injured patients.