Role of adrenergic signaling in fracture healing of non-osteoporotic and osteoporotic bone

• Applicant: Professorin Dr. Melanie Haffner-Luntzer
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 505623982

Osteoporosis is the most common metabolic bone disease characterized by low bone mass and increased fracture risk with almost half of all women and a quarter of all man above the age of 60 affected. Osteoporotic fractures are associated with immense suffering for the patient, longer hospitalization and high economic burden, because fracture healing is significantly delayed in osteoporotic patients. Experimental studies demonstrated an increased presence of inflammatory neutrophils in the early fracture hematoma and a delayed endochondral ossification process in osteoporotic mice. Therefore, there is the urgent need for new therapeutic strategies to improve osteoporotic bone healing. For that, a deeper understanding of the biology of fracture healing is required. During recent years, it became evident that the innervation of bone with sensory and sympathetic nerve fibers plays a crucial role during fracture healing. There is also growing evidence that local catecholamine signaling, especially adrenergic signaling, might play a role in the pathomechanisms of osteoporosis. In preliminary work for this proposal, we identified adrenergic signaling as one of the most enriched pathways in RNASeq analysis from fracture callus tissue of non-osteoporotic versus osteoporotic mice. Further, our results suggest that neutrophil recruitment to the early fracture hematoma is dependent on beta-adrenergic signaling and that chondrocyte-to-osteoblast transdifferentiation is diminished by catecholamine treatment. Therefore, the main hypothesis of the proposed project is that adrenergic signaling, mainly beta2-adrenoreceptor signaling, is involved in recruitment of inflammatory neutrophils to the fracture hematoma and plays a crucial role during the endochondral ossification process. We further hypothesize that adrenergic signaling is involved in the pathogenesis of compromised fracture healing in osteoporotic mice. Open questions which should be addressed by the proposed project are how systemic and local catecholamine levels change after a fracture event and during the course of fracture healing in non-osteoporotic and osteoporotic mice. We will further determine which adrenoreceptor (AR) might play the most important role during recruitment and activation of immune cells after fracture and if neutrophils are direct target cells of beta2-AR signaling. Additionally, we will analyze the influence of specific AR blockers on endochondral bone formation and if chondrocytes are direct target cells of beta2-AR signaling during fracture healing in non-osteoporotic and osteoporotic bone. On the molecular level, we will identify downstream pathways of adrenergic signaling during bone healing. The results of the proposed project might be clinically relevant to establish new treatment options for fracture healing complications.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Stefan O. Reber