Thigh bone (femur) of a mouse. Credits: Melanie Haffner-Luntzer, University Medical Center Ulm
A study at the University of Ulm and its medical center has uncovered the molecular mechanisms by which psychological trauma and other highly stressful experiences delay the healing of bone fractures.
The research team, which included scientists from Canada and Japan, was able to show that certain immune cells respond to stress by producing an enzyme, which in turn promotes the release of stress hormones. These stress hormones act locally on the bone where they inhibit the conversion of cartilage cells into bone cells, slowing down bone growth and fracture healing.
Aid workers experience enormous stress, as do victims of natural disasters and violence. In the event of a serious injury, this is not without consequences. It is already known that highly stressful and traumatic experiences delay the healing of wounds and bones.
Researchers at the University Medical Center Ulm have now uncovered the molecular mechanism underlying the negative effects of stress on bone metabolism and regeneration.
“Consistently high mental stress levels cause certain immune cells to produce an enzyme, which in turn triggers the production and release of stress hormones that compromise bone growth,” Professor Stefan Reber summarized their findings. The neurobiologist, head of the Laboratory of Molecular Psychosomatics at the Department of Psychosomatic Medicine and Psychotherapy in Ulm, coordinated the research together with Professor Melanie Haffner-Luntzer from the Institute for Orthopedic Research and Biomechanics. They published their work in the magazine Nature communication.
The responsible immune cells are so-called neutrophil granulocytes, which belong to the white blood cells and thus to the non-specific, innate immune system. Severe mental stress causes these immune cells to produce the enzyme tyrosine hydroxylase (TH). This enzyme then activates the local production and release of certain stress hormones (catecholamines) in the fracture hematoma. Adrenaline belongs to the group of catecholamines, as well as the precursors noradrenaline and dopamine. These locally secreted stress hormones act on the areas where new bone material should grow. To form new bone, cartilage cells are converted into bone cells.
“The effect of these stress hormones hinders this transition from cartilage to bone, slowing down bone growth and fracture healing,” explains Dr Miriam Tschaffon-Müller. The scientist from the Institute for Orthopedic Research and Biomechanics is one of the two first authors of the study, along with Elena Kempter, a doctoral researcher in Reber’s lab.
Using cell-type-specific knockout mice with suppressed TH expression and blocked adrenoceptors, the scientists were able to reveal this stress-induced mechanism of action at the molecular genetic level. The knockout mice showed no stress-induced inhibition of bone healing. In the clinical portion of the study, the researchers collaborated with the Department of Orthopedic Trauma, Hand, Plastic, and Reconstruction Surgery and the Department of Psychosomatic Medicine and Psychotherapy to examine patients with ankle fractures.
“The result of the clinical study showed: When the psychological burden caused by stress, trauma or depression was considered high, patients were also characterized by high levels of tyrosine hydroxylase (TH) in the fracture hematoma and impaired fracture healing,” says Haffner-Luntzer . What is especially astonishing: the decisive factor for these measurable effects was the patients’ subjective assessment of the mental stress load and their pain perception.
The study’s findings may have implications for clinical practice, making them directly relevant. For example, it may be advisable to consider the patient’s stress or trauma history when treating fractures and other major injuries. Under certain circumstances, it may be useful to use beta-blockers to dampen the negative influence of stress hormones on bone healing.
More information:
Miriam EA Tschaffon-Müller et al, Neutrophil-derived catecholamines mediate negative stress effects on bone, Nature communication (2023). DOI: 10.1038/s41467-023-38616-0
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