Analgesia via blockade of NGF/TrkA signaling does not influence fracture healing in mice

Rapp, Anna E.; Kroner, Jochen; Baur, Susanne; Schmid, F; Walmsley, Adrian R.; Mottl, Harald; Ignatius, Anita

doi:10.1002/jor.22892

Cited by 36 publications

(48 citation statements)

References 24 publications

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“…This result was supported by previous studies that the administration of pyridoxine selectively causes the damage in the large-diameter A-cells of the DRG with larger-diameter myelinated fibers in the sciatic nerve [ 20 , 27 , 28 ]. In our studies, we also observed the vulnerability of large-sized neurons after pyridoxine intoxication in DRG of dogs [ 25 , 26 , 29 , 30 ].…”

Section: Discussionmentioning

confidence: 61%

SP, CGRP changes in pyridoxine induced neuropathic dogs with nerve growth factor gene therapy

et al. 2016

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BackgroundNerve growth factor (NGF) is known not only as a major factor for neuronal plasticity but also as a pain stimulator. Although there have been several trials with NGF for its application in the regeneration or protection of the nervous system, the pain induced by NGF remains a challenge to be overcome. In this study, the pain induced by NGF gene therapy was evaluated.ResultsVehicle or recombinant dog NGF plasmid was administered into the intrathecal space of dogs. Twenty-four hours after the vehicle or NGF plasmid inoculation, dogs were subcutaneously treated with 150 mg/kg pyridoxine every day for 7 days. For pain assessment, physical examination and electrophysiological recording were performed. Only in the vehicle-treated group, weight loss occurred, while NGF plasmid inoculation significantly improved this physical abnormalities. In the vehicle-treated group, electrophysiological recordings showed that H-reflex disappeared at 24 h after the last pyridoxine treatment. However, in the NGF plasmid inoculated group, the H-reflex were normal. In the results of immunohistochemistry, the NGF plasmid administration efficiently expressed in the dorsal root ganglia and significantly increased the pyridoxine-induced reduction of calcitonin gene-related peptide (CGRP) immunoreactive neurons, but not in substance P immunoreactive neurons, in the dorsal root ganglia.ConclusionsGiven these results, we reason that NGF gene therapy in pyridoxine induced neuropathic dogs does not induce neuropathic pain with this dosage, even with increasing the expression of CGRP.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-015-0236-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 61%

SP, CGRP changes in pyridoxine induced neuropathic dogs with nerve growth factor gene therapy

et al. 2016

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“…Moreover, our previous studies in mouse long bone development showed that interruption of perichondrium-derived NGF expression or sensory nerve-associated TrkA activity impairs a sequence of events in long bone ossification, including impeding the expansion of osterix-expressing progenitor cell numbers and blunting vascular ingrowth (10). Given our data demonstrating the critical role of TrkA signaling in bone morphogenesis and repair, it is not clear why experimental work with neutralizing antibodies against NGF have not shown a significant delay in bone healing (28,29). It is possible that the analgesic effects of anti-NGF are observed at a much lower dose than the effects needed to impede tissue repair.…”

Section: Discussionmentioning

confidence: 87%

Fracture repair requires TrkA signaling by skeletal sensory nerves

Zhu¹,

Meyers²,

Chang³

et al. 2019

Journal of Clinical Investigation

131

196

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“…In combination with the pro-osteoclastic factors released by MC2 discs, this may cause a high bone turn-over as described in microarchitectural analysis of MC biopsies 29 . Importantly, skeletal pain after fracture and osteoarthritic pain and bone destruction can be reduced with Trk blockage without inhibiting fracture healing 38,41–44 . Similar to bone callus, MC endplates show high numbers of PGP-9.5 nerve fibers 9,10 .…”

Section: Discussionmentioning

confidence: 99%

ISSLS PRIZE IN BASIC SCIENCE 2017: Intervertebral disc/bone marrow cross-talk with Modic changes

et al. 2017

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Study design Cross-sectional cohort analysis of patients with Modic Changes (MC). Objective Our goal was to characterize the molecular and cellular features of MC bone marrow and adjacent discs. We hypothesized that MC associate with biologic cross-talk between discs and bone marrow, the presence of which may have both diagnostic and therapeutic implications. Background Data MC are vertebral bone marrow lesions that can be a diagnostic indicator for discogenic low back pain. Yet, the pathobiology of MC is largely unknown. Methods Patients with Modic type 1 or 2 changes (MC1, MC2) undergoing at least 2-level lumbar interbody fusion with one surgical level having MC and one without MC (control level). Two discs (MC, control) and two bone marrow aspirates (MC, control) were collected per patient. Marrow cellularity was analyzed using flow cytometry. Myelopoietic differentiation potential of bone marrow cells was quantified to gauge marrow function, as was the relative gene expression profiles of the marrow and disc cells. Disc/bone marrow cross-talk was assessed by comparing MC disc/bone marrow features relative to unaffected levels. Results Thirteen MC1 and eleven MC2 patients were included. We observed pro-osteoclastic changes in MC2 discs, an inflammatory dysmyelopoiesis with fibrogenic changes in MC1 and MC2 marrow, and upregulation of neurotrophic receptors in MC1 and MC2 bone marrow and discs. Conclusion Our data reveal a fibrogenic and pro-inflammatory cross-talk between MC bone marrow and adjacent discs. This provides insight into the pain generator at MC levels and informs novel therapeutic targets for treatment of MC-associated LBP.

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Analgesia via blockade of NGF/TrkA signaling does not influence fracture healing in mice

Cited by 36 publications

References 24 publications

SP, CGRP changes in pyridoxine induced neuropathic dogs with nerve growth factor gene therapy

SP, CGRP changes in pyridoxine induced neuropathic dogs with nerve growth factor gene therapy

Fracture repair requires TrkA signaling by skeletal sensory nerves

ISSLS PRIZE IN BASIC SCIENCE 2017: Intervertebral disc/bone marrow cross-talk with Modic changes

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