gms | German Medical Science

Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2015)

20.10. - 23.10.2015, Berlin

Analgesia Via Blockade of NGF/TrkA Signaling Does Not Influence Fracture Healing in Mice

Meeting Abstract

  • presenting/speaker Anna Rapp - Institut für Unfallchirurgische Forschung und Biomechanik, Universität Ulm, Zentrum für Muskuloskelettale Forschung Ulm, Ulm, Germany
  • Jochen Kroner - Institut für Unfallchirurgische Forschung und Biomechanik, Universität Ulm, Zentrum für Muskuloskelettale Forschung Ulm, Ulm, Germany
  • Stephanie Baur - Institut für Unfallchirurgische Forschung und Biomechanik, Universität Ulm, Zentrum für Muskuloskelettale Forschung Ulm, Ulm, Germany
  • Fabian Schmid - Institut für Unfallchirurgische Forschung und Biomechanik, Universität Ulm, Zentrum für Muskuloskelettale Forschung Ulm, Ulm, Germany
  • Adrian Walmsley - Glenmark Pharmaceuticals Ltd., La Cheux-de-Fonds, Switzerland
  • Harald Mottl - Glenmark Pharmaceuticals Ltd., La Cheux-de-Fonds, Switzerland
  • Anita Ignatius - Institut für Unfallchirurgische Forschung und Biomechanik, Universität Ulm, Zentrum für Muskuloskelettale Forschung Ulm, Ulm, Germany

Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2015). Berlin, 20.-23.10.2015. Düsseldorf: German Medical Science GMS Publishing House; 2015. DocPO22-267

doi: 10.3205/15dkou715, urn:nbn:de:0183-15dkou7159

Veröffentlicht: 5. Oktober 2015

© 2015 Rapp et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Objectives: Abatement of fracture-related pain is important in patient welfare. However, currently available analgesics, including non-steroidal anti-inflammatory drugs, are considered to impair fracture healing through blockade of cyclooxygenase-2 (Krischak et al. 2007, Arch Orthop Trauma Surg). An alternative for fracture-related pain treatment may be blockade of nerve growth factor (NGF)/neurotrophic tyrosine kinase receptor type 1 (TrkA) signaling. Blockade of this pathway using an anti-NGF antibody was shown to be effective for the treatment of chronic low back pain and arthrosis (Katz et al. 2011, Pain; McKelvey et al. 2013, J Neuroscience). Because the effect of blocking this signal-pathway on bone healing has not been extensively investigated, we addressed this issue by applying neutralizing antibodies that target NGF and TrkA, respectively, in a mouse fracture model.

Methods: Male mice with a knock-in for human TrkA received a femur-osteotomy stabilized by an external fixator and were randomly allocated to phosphate-buffered-saline, anti-NGF-antibody or anti-TrkA-antibody treatment (73 mice in total). The substances were administered intraperitoneally on day 1, 6 and 11 post surgery; the antibodies were applied at a dosage of 10 mg/kg bodyweight. The analgesic effect of the antibodies was determined from the activity of the mice and the ground reaction force (GRF) of the operated limb on day 2, 5, 7 14 and 20 post surgery. The mice were sacrificed on days 7, 14 and 25. The effect of antibody administration on fracture healing was assessed by histomorphometry, micro-computed tomography and biomechanics. To test for statistical significance, ANOVA and post-hoc Fisher's LSD test were applied.

Results and Conclusion: We did not detect significant differences in the callus composition or maturation when applying anti-NGF or anti-TrkA antibody compared to PBS treatment. Furthermore, the GRF during the observation period and the biomechanical properties of the healed femurs were not significantly altered. However, mice treated with anti-TrkA antibody displayed significantly greater activity on post-operative day 2 compared to PBS treatment (+ 68 %; p = 0.007), indicating effective analgesia.

In conclusion, our results indicate no negative effect of a blockade of NGF/TrkA signaling on fracture healing in rodents using specific antibodies because biomechanical properties and the callus composition were unaltered by antibody treatment. Our data may encourage a clinical study to investigate whether a blockade of NFG/TrkA signaling using specific antibodies to achieve analgesia is an alternative to recently available analgesics for the treatment of fracture pain in humans.