Chronic psychosocial stress compromises the immune response and endochondral ossification during bone fracture healing via β-AR signaling

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-04, Vol.116 (17), p.8615-8622
• Main Authors: Haffner-Luntzer, Melanie, Foertsch, Sandra, Fischer, Verena, Prystaz, Katja, Tschaffon, Miriam, Mödinger, Yvonne, Bahney, Chelsea S., Marcucio, Ralph S., Miclau, Theodore, Ignatius, Anita, Reber, Stefan O.
• Format: Article
• Language: English
• Subjects: Adrenergic receptors; Angiogenesis; Animals; Biocompatibility; Biological Sciences; Biomedical materials; Bone healing; Bone marrow; Callus; Cartilage; Chronic Disease; Disease Models, Animal; Endochondral bone; Femur; Fracture Healing - immunology; Fracture Healing - physiology; Fractures; Healing; Hematoma; Housing; Immune response; Immune system; Inflammation - immunology; Inflammation - physiopathology; Inflammatory diseases; Inflammatory response; Leukocytes (neutrophilic); Lymphocytes; Lymphocytes T; Male; Mental disorders; Mice; Mice, Inbred C57BL; Neutrophils; Ossification; Osteogenesis - immunology; Osteogenesis - physiology; Osteotomy; PNAS Plus; Post traumatic stress disorder; Propranolol; Psychological stress; Receptors, Adrenergic, beta - immunology; Receptors, Adrenergic, beta - metabolism; Risk analysis; Risk factors; Signal Transduction - immunology; Signal Transduction - physiology; Signaling; Social interactions; Stiffness; Stress, Psychological - immunology; Stress, Psychological - physiopathology; Trauma
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1819218116

Chronic psychosocial stress/trauma represents an increasing burden in our modern society and a risk factor for the development of mental disorders, including posttraumatic stress disorder (PTSD). PTSD, in turn, is highly comorbid with a plethora of inflammatory disorders and has been associated with increased bone fracture risk. Since a balanced inflammatory response after fracture is crucial for successful bone healing, we hypothesize that stress/trauma alters the inflammatory response after fracture and, consequently, compromises fracture healing. Here we show, employing the chronic subordinate colony housing (CSC) paradigm as a clinically relevant mouse model for PTSD, that mice subjected to CSC displayed increased numbers of neutrophils in the early fracture hematoma, whereas T lymphocytes and markers for cartilage-to-bone transition and angiogenesis were reduced. At late stages of fracture healing, CSC mice were characterized by decreased bending stiffness and bony bridging of the fracture callus. Strikingly, a single systemic administration of the β-adrenoreceptor (AR) blocker propranolol before femur osteotomy prevented bone marrow mobilization of neutrophils and invasion of neutrophils into the fracture hematoma, both seen in the early phase after fracture, as well as a compromised fracture healing in CSC mice. We conclude that chronic psychosocial stress leads to an imbalanced immune response after fracture via β-AR signaling, accompanied by disturbed fracture healing. These findings offer possibilities for clinical translation in patients suffering from PTSD and fracture.