Background/Purpose: Rheumatoid Arthritis (RA) is an autoimmune disease very commonly associated with chronic pain which is often resistant to currents analgesics. Targeting Nerve Growth Factor (NGF), a neurotrophic factor, is already considered a very promising treatment of RA. However, it could lead to serious adverse effects. Our aim is to better understand the involvement of the specific intracellular signaling pathways activated by NGF through the tyrosine kinase type A (TrkA) receptor, in the pathophysiology of RA especially those involved in associated chronic pain.

Methods:

We performed a multimodal study in TrkA/C knock-in mice expressing a chimeric receptor formed by the native extracellular part of TrkA and the functional transmembrane and intracellular part of the tyrosine kinase type C receptor (TrkC) which binds neurotrophin 3 (NT3). We investigated nociceptive behavior such as mechanical allodynia and thermal hyperalgesia using von Frey and paw immersion test in CFA induced-arthritis model. In vivo cartilage and bone remodeling were assessed by scintigraphic imaging using ^99mTc-NTP 15-5 and ^99mTc-HMDP radiotracers, respectively. CD68 positive cell infiltration and CGRP positive nerve fibers sprouting were assessed in the joint as well as TrkA and ASIC3 expression in DRG cells bodies using an immunohistochemical approach. We are currently investigating the intracellular pathway potentially involved at the DRG level.

Results: Our results showed a specific lack of mechanical allodynia development while thermal hyperalgesia was unaffected in TrkA/C monoarthritic mice compared to WT littermates. This change in pain behavior was associated with a specific decrease of ^99mTc-HMDP in TrkA/C monoarthritic mice, suggesting a unique change in bone remodeling. Indeed, cartilage remodeling was similar between both genotypes. We also observed a decrease of CD68-positive cell infiltration as well as CGRP expression in the inflamed joint in TrkA/C mice compared to WT mice while the expression of TrkA and ASIC3 in the DRGs was unaffected between both genotypes following monoarthritis.

Conclusion:

The present study demonstrates a specific involvement of NGF/TrkA signaling in pain, especially mechanical hypersensitivity and also bone remodeling in inflammatory arthritis. We are now investigated the specific intracellular pathway involved.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/involvement-of-receptor-tyrosine-kinase-a-signaling-in-rhumatoid-arthritis-using-trkac-knock-in-mice-a-multimodal-approach/