Mast Cells Drive Systemic Inflammation and Compromised Bone Repair After Trauma

Abstract

There is evidence that mast cells contribute to inflammation induced by hemorrhagic shock, severe tissue injury or sepsis. Mast cells are highly responsive to alarm signals generated after trauma, and release many inflammatory mediators including interleukin-6, a key mediator of posttraumatic inflammation. An overwhelming posttraumatic inflammation causes compromised bone healing; however, the underlying cellular and molecular mechanisms are poorly understood. Recently, we found that mast cells trigger local and systemic inflammation after isolated fracture leading to uneventful bone repair. Here, we investigated whether mast cells critically contribute to trauma-induced compromised bone healing. Male Mcpt5-Cre+ R-DTA mice, which lack connective tissue type mast cells, and their mast cell-competent Cre− littermates underwent a femur fracture with/without thoracic trauma. Posttraumatic systemic and local inflammation and bone repair were assessed 3 h and 21 d post injury. Both, the systemic and pulmonary inflammation was significantly increased in mast cell-competent mice upon combined trauma compared to isolated fracture. In mast cell-deficient mice, the increase of inflammatory mediators in the circulation induced by the severe trauma was abolished. In the bronchoalveolar lavage fluid, the trauma-induced increase of inflammatory cytokines was not reduced, but the neutrophil invasion into the lungs was significantly diminished in the absence of mast cells. Locally in the fracture hematoma, mast cell-competent mice displayed reduced inflammatory mediator concentrations after combined trauma compared to isolated fracture, which was abolished in mast cell-deficient mice. Notably, while combined trauma resulted in compromised bone repair in mast cell-competent mice, indicated by significantly reduced bone and increased cartilage fracture callus contents, this was abolished in Mcpt5-Cre+ R-DTA mice. Therefore, mast cells contribute to trauma-induced compromised bone repair and could be a potential target for new treatment options to improve fracture healing in multiply injured patients.

High Systemic Immune-Inflammation Index and Body Mass Index Are Independent Risk Factors of the Thoracic Ossification of the Ligamentum Flavum

“…Inflammation and abnormal immunity have been demonstrated to play important roles in the pathogenesis of degenerative musculoskeletal diseases, such as intervertebral disc degeneration and osteoarthritis [ 24 , 25 ]. Furthermore, patients with fractures suffer from severe inflammation caused by their fractures [ 26 , 27 ]. Therefore, patients receiving herniorrhaphy for reducible inguinal or femoral hernia from March 2020 to March 2021 at our hospital were selected as the controls in the control group.…”

Tibial bone strength is negatively affected by volumetric muscle loss injury to the adjacent muscle in male mice

“…First, there is a well-established inflammatory phase associated with VML injury 49,50 that can spill into the systemic vasculature, 51 and systemic inflammation has been linked to bone loss in fracture models 52 and inflammatory diseases. 53,54 Second, our bone-to-muscle ratios were different between VML-injured and uninjured limbs suggesting that the functional capacities of the bone and muscle were not appropriately matched. For example, in uninjured limbs there was ~0.6 N of tibial bone ultimate load per 1 mN m plantarflexion torque, and this ratio was similar in both Uninjured-12 and Uninjured-20 limbs.…”

“…We cannot completely rule out the future of bone wasting as a potential comorbid pathology with VML injury because our study only involved animals during their natural developmental stage. First, there is a well‐established inflammatory phase associated with VML injury 49,50 that can spill into the systemic vasculature, 51 and systemic inflammation has been linked to bone loss in fracture models 52 and inflammatory diseases 53,54 . Second, our bone‐to‐muscle ratios were different between VML‐injured and uninjured limbs suggesting that the functional capacities of the bone and muscle were not appropriately matched.…”

Altered early immune response after fracture and traumatic brain injury

“…Interestingly, it has been shown in the context of fracture healing, that mast cell-derived CXCL10 contributes to increased osteoclastogenesis in the fracture callus in osteoporotic mice after femur fracture ( 25 ). Mast cell-deficient mice displayed less osteoclasts in the fracture callus, a reduced callus remodelling ( 24 ) and were protected from delayed fracture healing after ovariectomy ( 25 ) and additional thoracic trauma ( 44 ). This indicates a critical role of mast cells during fracture healing and might suggest that reduced mast cell numbers could have positive effects on the healing process regarding callus bone mass, although of course callus remodeling during later healing phases is also important for fracture healing outcome in patients.…”

“…Species-specific non-targeting immunoglobulins were used as isotype controls. We have demonstrated previously that Avidin is a very good tool to stain mast cells in tissue sections in various animal models ( 24 , 25 , 44 , 45 ).…”