Linking traumatic brain injury and accelerated bone regeneration - a central role of alpha-adrenergic/CGRP signaling.

将创伤性脑损伤与加速骨再生联系起来——α-肾上腺素能/CGRP 信号传导的核心作用。

• 批准号: 326880412
• 负责人: Professor Dr. Johannes Keller, Ph.D.
• 金额: --
• 依托单位: Sektion Experimentelle Unfallchirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/326880412?language=en
• 关键词: Linking; traumatic; brain; injury; accelerated

Impaired fracture healing represents an ongoing clinical challenge, as treatment options remain limited. Therefore, the mechanistic understanding why traumatic brain injury (TBI) positively affects fracture repair holds great therapeutic potential. Using an experimental approach, we previously demonstrated that callus formation is increased in a mouse model combining surgically induced TBI and fracture of the femur. In our current work, we were able to elucidate the complex pathophysiologic processes linking TBI and bone regeneration in more detail. As a potential key element, we were able to identify increased alpha-adrenergic/CGRP signaling, which mediates accelerated bone regeneration following TBI. Specifically, we propose that TBI results in a temporary rise in sympathetic tone, resulting in norepinephrine (NE) release from nerve endings in the bone microenvironment. In intact bone, this leads to the inhibition of bone formation through beta-adrenergic signaling. In fractured bone however, the temporary rise of NE following TBI promotes bone regeneration through the activation of alpha-adrenergic receptors, the stimulation of local CGRP synthesis, and the activation of osteoblast precursors. Our current results raise specific questions that need to be address in order to fully understand the regulatory circuits linking bone and brain injury. The proposed study on the crosstalk between TBI and bone regeneration, as well as the comprehension of alpha-adrenergic/CGRP signaling as its putative central element, may aid in developing new therapeutic strategies for patients suffering from impaired fracture repair.

由于治疗选择仍然有限，骨折愈合受损是一个持续的临床挑战。因此，从机制上理解为什么创伤性脑损伤（TBI）对骨折修复有积极影响具有巨大的治疗潜力。我们之前通过实验方法证明，在手术诱导的 TBI 和股骨骨折相结合的小鼠模型中，愈伤组织的形成有所增加。在我们目前的工作中，我们能够更详细地阐明 TBI 和骨再生之间的复杂病理生理过程。作为一个潜在的关键因素，我们能够识别出增加的 α-肾上腺素能/CGRP 信号传导，该信号传导 TBI 后加速骨再生。具体来说，我们认为 TBI 会导致交感神经张力暂时升高，导致骨微环境中的神经末梢释放去甲肾上腺素 (NE)。在完整的骨骼中，这会通过β-肾上腺素能信号传导抑制骨形成。然而，在骨折中，TBI 后 NE 的暂时升高可通过激活 α-肾上腺素能受体、刺激局部 CGRP 合成以及激活成骨细胞前体细胞来促进骨再生。我们目前的结果提出了需要解决的具体问题，以便充分了解骨和脑损伤之间的调节回路。拟议的关于 TBI 和骨再生之间的串扰的研究，以及对 α-肾上腺素能/CGRP 信号传导作为其假定中心要素的理解，可能有助于为骨折修复受损的患者制定新的治疗策略。