Article
Analgesia Via Blockade of NGF/TrkA Signaling Does Not Influence Fracture Healing in Mice
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Published: | October 5, 2015 |
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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.