Timing matters - The impact of the circadian clock on fracture healing

• Applicant: Dr. Denise Jahn
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 524847996

Impaired healing occurs in up to 10% of all fractures, leading to pain, long-term reduction in the quality of life and high socio-economic costs. Until now, the treatment options are limited, raising the need for new drugs that can be applied to patients with impaired fracture healing. Here, the circadian clock represents a promising target mechanism, as it regulates the bone metabolism, affecting osteoblasts, osteoclasts and osteocytes in vivo and in vitro. Moreover, disruption of the circadian rhythm through shift work or sleep restriction leads to reduced bone formation and decreased bone mineral density. Now, our preliminary experiments show a strong impairment of bone healing in mice with a genetic disruption of the circadian clock reinforcing the need for further research. Within the first work package (WP) of the present project, I will analyze the molecular pathways of the reduced healing in mice with a global disrupted circadian clock through stress hormone measurement, gene expression studies and histological analysis. The second WP will utilize a mouse model with a deletion of the circadian clock solely in the brain, with the circadian clocks in the bone cells staying genetically intact. This model simulates the condition following shift work or traumatic brain injury and will reveal first insights into the risk of these patients for disturbed fracture healing that will be further validated in a retrospective clinical trial in WP4. Moreover, the specific depletion of the circadian clock in osteoblasts will enlighten local mechanisms. In the third WP the impact of the specific time point of surgery on the healing outcome will be analyzed in man and mouse. Finally, if the progress of WP1-4 allows, in the last work package experimentally approved compounds of the circadian clock will be applied in vivo to improve healing outcome. The proposed research program holds great potential to aid in developing novel therapeutic approaches for the treatment of patients with impaired fracture healing, identify risk patients for delayed healing and optimize the time point of elective surgeries and drug application. In addition, this application renders me the possibility to establish myself as independent scientist and to strengthen my own research profile.

• DFG Programme: Research Grants
• International Connection: Canada, Greece
• Cooperation Partners: Professor Efstathios Chronopoulos, Ph.D.; Professor Dr. Michael Fehlings