Rapp Anna E, Kroner Jochen, Baur Stephanie, Schmid Fabian, Walmsley Adrian, Mottl Harald, Ignatius Anita
Institute of Orthopaedic Research and Biomechanics, Centre of Musculoskeletal Research Ulm (zmfu), University of Ulm, Ulm, Germany.
Glenmark Pharmaceuticals Limited, La Chaux-de-Fonds, Switzerland.
J Orthop Res. 2015 Aug;33(8):1235-41. doi: 10.1002/jor.22892. Epub 2015 May 7.
Abatement of fracture-related pain is important in patient welfare. However, the frequently used non-steroidal anti-inflammatory drugs are considered to impair fracture healing through blockade of cyclooxygenase-2. An alternative for fracture-related pain treatment may be blockade of nerve growth factor (NGF)/neurotrophic tyrosine kinase receptor type 1 (TrkA) signaling. 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. Mice with a knock-in for human TrkA underwent femur osteotomy and were randomly allocated to phosphate-buffered-saline, anti-NGF-antibody, or anti-TrkA-antibody treatment. The analgesic effect of the antibodies was determined from the activity and the ground reaction force of the operated limb. The effect of antibody administration on fracture healing was assessed by histomorphometry, micro-computed tomography, and biomechanics. NGF/TrkA-signaling blockade had no negative effect on fracture healing as callus formation and maturation were not altered. Mice treated with anti-TrkA antibody displayed significantly greater activity on post-operative day 2 compared to PBS treatment indicating effective analgesia. Our data indicate, that blockade of NGF/TrkA signaling via specific neutralizing antibodies for pain reduction during fracture healing does not influence fracture healing.
减轻骨折相关疼痛对患者的健康至关重要。然而，常用的非甾体抗炎药被认为会通过阻断环氧化酶-2来损害骨折愈合。治疗骨折相关疼痛的一种替代方法可能是阻断神经生长因子（NGF）/神经营养性酪氨酸激酶受体1型（TrkA）信号传导。由于阻断该信号通路对骨愈合的影响尚未得到广泛研究，我们通过在小鼠骨折模型中分别应用靶向NGF和TrkA的中和抗体来解决这个问题。携带人TrkA基因敲入的小鼠接受股骨截骨术，并随机分配至磷酸盐缓冲盐水、抗NGF抗体或抗TrkA抗体治疗组。根据手术肢体的活动度和地面反作用力来确定抗体的镇痛效果。通过组织形态计量学、显微计算机断层扫描和生物力学评估抗体给药对骨折愈合的影响。NGF/TrkA信号传导阻断对骨折愈合没有负面影响，因为骨痂形成和成熟未发生改变。与磷酸盐缓冲盐水治疗相比，接受抗TrkA抗体治疗的小鼠在术后第2天表现出明显更大的活动度，表明镇痛效果良好。我们的数据表明，在骨折愈合过程中，通过特异性中和抗体阻断NGF/TrkA信号传导以减轻疼痛不会影响骨折愈合。
