# Involvement of Nerve Growth Factor and Tyrosine Kinase type A Receptor signaling pathways in Arthritis in knock-in TrkA/C mice: multimodal approach

Lauriane Delay, Julie Barbier, Ludivine Boudieu, Youssef Aissouni, Denis

Ardid, A. Briat, Philippe Auzeloux, Elisabeth Miot-Noirault, Aziz Moqrich, Fabien Marchand

► To cite this version:

Lauriane Delay, Julie Barbier, Ludivine Boudieu, Youssef Aissouni, Denis Ardid, et al. Involvement of Nerve Growth Factor and Tyrosine Kinase type A Receptor signaling pathways in Arthritis in knock-in TrkA/C mice: multimodal approach. ACR/ARHP Annual Meeting, Nov 2017, San Diego (CA), United States. . [hal-04849290](https://hal HAL Id: [hal-04849290](https://uca.hal.science/hal-04849290v1)

Submitted on 19 Dec 2024

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# Involvement of Receptor Tropomyosin Kinase type A signaling in Rheumatoid Arthritis using TrkA/C knock-in mice: a multimodal approach

Delay L, Barbier J, Boudieu L, Aissouni Y, Ardid D, Briat A, Auzeloux P, Miot-Noirault E, Moqrich A, Marchand F

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La Région
Auvergne-Rhône-Alpes

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Inserm

Contact: lauriane delays@free.fr

## Introduction

Rheumatoid Arthritis (RA) is an autoimmune disease characterized by articular inflammation, cartilage and bone alterations and is commonly associated with chronic pain which is often refractory to currents analgesics.

Targeting Nerve Growth Factor (NGF), a neurotrophic factor, is considered a very promising treatment for RA. However, it could lead to serious adverse effects.

Our aim is to better understand the involvement of specific intracellular signaling pathways activated by NGF through its receptor, the tropomyosine kinase type A (TrkA), in the pathophysiology and associated pain symptoms of RA in order to discover more specific targets.

## Material & Methods

Genetic model: TrkA/C chimeric knock-in mice

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Study design:

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Scintigraphic imaging:

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* Bone remodeling: ⁹⁹mTc-hydroxymethylene diphosphonate (HMDP)

* Cartilage remodeling: ⁹⁹mTc-N-(triéthylammonium)-3-propyl-[15]ane-N5 (NTP 15-5)

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Immunohistochemistry of the joint:

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* Anti-cluster of differentiation 68 (CD68) => monocytes, macrophages, osteoclasts lineage

* Anti-calcitonin gene related peptide (CGRP) => peptidergic nerve fibers

## Results

<figure><img src="image_17.png" /><figcaption>Figure 2: TrkA/C knock-in mice exhibit a specific loss of mechanical hypersensitivity (allodynia and weight bearing) compared to WT mice following arthritis</figcaption></figure>

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<figure><img src="image_19.png" /><figcaption>Two way ANOVA/Tukey post-hoc test, ** = p < 0,01; *** = p < 0,001 compared to WT Sham</figcaption></figure>

<figure><img src="image_20.png" /><figcaption>Figure 3: Increase in bone but not cartilage remodeling is reduced in TrkA/C knock-in mice compared to WT mice following arthritis</figcaption></figure>

<figure><img src="image_21.png" /><figcaption>Two way ANOVA/Tukey post-hoc test, * = p < 0,05; ** = p < 0,01; *** = p < 0,001 compared to WT Sham, ∞ = p < 0,01; ∞∞ = p < 0,001 compared to WT MoAr</figcaption></figure>

<figure><img src="image_22.png" /><figcaption>Figure 5: Lack of peripheral peptidergic fibers sprouting in TrkA/C knock-in mice compared to WT mice 14 days after arthritis</figcaption></figure>

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## Conclusions

Taken together, our results show a specific role of TrkA receptor signaling activated by NGF in pain symptoms with a specific impact on **mechanical hypersensitivity** which could be partially due to a change in **peptidergic innervation** of the joint and sprouting following arthritis. Finally, loss of TrkA signaling pathways activation seems to impact **bone remodeling** following arthritis. We are currently investigating the TrkA signaling pathways involved in pain at the level of the dorsal root ganglia and in bone remodeling in osteoclast cultures.