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

• Applicants: Professor Dr. Johannes Keller; Privatdozent Serafeim Tsitsilonis, Ph.D.
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2016 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 326880412

• Final Report Year: 2024

Final Report Abstract

In the search for novel approaches to pharmacologically treat fracture nonunion, the current study investigated the unique clinical phenomenon that traumatic brain injury (TBI) improves fracture healing while causing bone loss in the uninjured skeleton. We first found that the hyperadrenergic state after TBI inhibits bone formation by osteoblasts and stimulates bone resorption by osteoclasts in the uninjured skeleton in an Adrb2-dependent manner, explaining systemic bone loss after TBI. These data essentially extend the clinical implications of the previous groundbreaking work, primarily by Gerard Karsenty's group, which demonstrated a regulatory role of Adrb2 on osteoblast and osteoclast function at multiple levels. Second, even more importantly, and in sharp contrast to its hitherto established function in the skeleton, we found that Adrb2 signaling is a positive regulator of fracture healing. Here, Adrb2 is highly expressed in periosteal cells where it induces the expression of VEGF and CGRP, both of which synergistically promote the formation of osteogenic type-H vessels. Thus, a hyperadrenergic state after TBI enhances vascularization of the fracture callus and promotes bone healing in an Adrb2-dependent manner. Similarly, although Adrb2 does not profoundly affect fracture healing in young mice in which sympathetic tone is low, lack of Adrb2 in mice with age-related increase in sympathetic output results in avascular fracture nonunion. Finally, systemic application of the Adrb2 agonist formoterol, widely used clinically as an inhaled agent in asthma and COPD, accelerated fracture healing in a preclinical mouse model. Together, the results propose a novel function of Adrb2 signaling in the injured skeleton with high clinical relevance. They show that under conditions of increased sympathetic output, such as in TBI or, more commonly, as a physiological adaptation in the aging organism, Adrb2 signaling is an essential stimulus for adequate bone healing. Furthermore, the project shows that the neuropeptide CGRP, downstream of Adrb2, functions a critical driver of bone regeneration. Together, using preclinical mouse models, unbiased genome gene wide expression analyses and translational approaches, this project provides evidence that increased beta2-adrenergic/CGRP signaling is an essential and targetable stimulus of bone regeneration by regulating callus neovascularization.

Publications

• Anabolic Therapies in Osteoporosis and Bone Regeneration. International Journal of Molecular Sciences, 20(1), 83.
  Russow, Gabriele; Jahn, Denise; Appelt, Jessika; Märdian, Sven; Tsitsilonis, Serafeim & Keller, Johannes
  
• Crosstalk of Brain and Bone—Clinical Observations and Their Molecular Bases. International Journal of Molecular Sciences, 21(14), 4946.
  Otto, Ellen; Knapstein, Paul-Richard; Jahn, Denise; Appelt, Jessika; Frosch, Karl-Heinz; Tsitsilonis, Serafeim & Keller, Johannes
  
• The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing. eBioMedicine, 59, 102970.
  Appelt, Jessika; Baranowsky, Anke; Jahn, Denise; Yorgan, Timur; Köhli, Paul; Otto, Ellen; Farahani, Saeed Khomeijani; Graef, Frank; Fuchs, Melanie; Herrera, Aarón; Amling, Michael; Schinke, Thorsten; Frosch, Karl-Heinz; Duda, Georg N.; Tsitsilonis, Serafeim & Keller, Johannes
  
• Validation of reference genes for expression analysis in a murine trauma model combining traumatic brain injury and femoral fracture. Scientific Reports, 10(1).
  Otto, Ellen; Köhli, Paul; Appelt, Jessika; Menzel, Stefanie; Fuchs, Melanie; Bahn, Alina; Graef, Frank; Duda, Georg N.; Tsitsilonis, Serafeim; Keller, Johannes & Jahn, Denise
  
• Effects of CGRP receptor antagonism on glucose and bone metabolism in mice with diet-induced obesity. Bone, 143, 115646.
  Köhli, Paul; Appelt, Jessika; Otto, Ellen; Jahn, Denise; Baranowsky, Anke; Bahn, Alina; Erdmann, Cordula; Müchler, Judith; Mülleder, Michael; Tsitsilonis, Serafeim & Keller, Johannes
  
• Future Perspectives in Spinal Cord Repair: Brain as Saviour? TSCI with Concurrent TBI: Pathophysiological Interaction and Impact on MSC Treatment. Cells, 10(11), 2955.
  Köhli, Paul; Otto, Ellen; Jahn, Denise; Reisener, Marie-Jacqueline; Appelt, Jessika; Rahmani, Adibeh; Taheri, Nima; Keller, Johannes; Pumberger, Matthias & Tsitsilonis, Serafeim
  
• The selective norepinephrine reuptake inhibitor reboxetine promotes late-stage fracture healing in mice. iScience, 26(10), 107761.
  Donat, Antonia; Jiang, Shan; Xie, Weixin; Knapstein, Paul Richard; Albertsen, Lilly-Charlotte; Kokot, Judith Luisa; Sevecke, Jan; Augustin, Ruben; Jahn, Denise; Yorgan, Timur Alexander; Frosch, Karl-Heinz; Tsitsilonis, Serafeim; Baranowsky, Anke & Keller, Johannes