¹Julius Wolff Institut, Charité – Universitätsmedizin Berlin, Berlin, Deutschland
²Centrum für Muskuloskeletale Chirurgie, Charité – Universitätsmedizin Berlin, Berlin, Deutschland
³Klinik und Poliklinik für Unfallchirurgie und Orthopädie, Universitätsklinikum Hamburg-Eppendorf, Berlin, Deutschland
⁴Klinik für Mund-, Kiefer- und Gesichtschirurgie, Charité – Universitätsmedizin Berlin, Berlin, Deutschland
⁵Klinik für Mund-, Kiefer- und Gesichtschirurgie, Berlin, Deutschland

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Objectives and questions: Trauma to the central nervous system, like Traumatic brain injury (TBI) and spinal cord injury (SCI), causes post-traumatic bone loss, raising the fracture risk. These fractures significantly hinder rehabilitation and are associated with high mortality and morbidity in already compromised patients. Contributing factors include reduced mobility, systemic inflammation, hormone dysregulation, and deficiencies in calcium and vitamin D. Local impacts on bone forming osteoblasts following trauma might be transmitted through increased adrenergic signaling, which is known to regulate circadian activity in various cell types, including osteoblasts. Understanding adrenergic signaling's impact on osteoblast activity in the context of trauma could open new avenues for therapeutic interventions to prevent bone loss and improve outcomes for affected patients.

Material and methods: We investigated the effects of TBI and SCI on bone health using murine models. RNA was isolated from bone, hypothalamus, and adipose tissue for gene expression analysis. Bone structure was assessed using micro-computed tomography (µCT). To explore the role of adrenergic signaling in these injuries, we analyzed serum samples and validated findings in ADRB2-deficient mice. Additionally, the impact of disrupted circadian rhythms was examined in mice lacking Bmal1, a key circadian clock protein.

Results: Both TBI and SCI significantly downregulated the expression of osteoblast marker genes within the first week following injury, indicating an immediate adverse effect on bone metabolism. Concurrently, gene expression analysis revealed a robust metabolic activation of adipose tissue, which correlated with elevated adrenergic metabolites in serum. µCT analysis confirmed impairments in trabecular bone structure 14 days post-injury. Furthermore, ADRB2-deficient mice were protected from the detrimental effects of TBI, suggesting a central role for adrenergic signaling in post-traumatic bone loss. TBI also disrupted circadian gene expression in the hypothalamus, aligning with previous observations of altered day-night rhythms in central nervous system trauma patients. Locally, it was shown that adrenergic signaling via ADRB2 inhibits osteoblast activity through circadian rhythm modulation. Mice with disrupted circadian rhythms exhibited compromised bone structure, further supporting the link between adrenergic signaling and circadian disruption in bone metabolism.

Discussion and conclusions: Our findings suggest that traumatic injuries, particularly those involving the central nervous system, enhance adrenergic signaling, which negatively impacts bone formation. The ADRB2 receptor on osteoblasts may represent a promising therapeutic target for regulating rhythmic activity of these cells. Targeting this pathway could offer novel strategies to prevent post-traumatic bone loss and improve the long-term quality of life for trauma patients.