期刊
PAIN
卷 163, 期 7, 页码 E837-E849出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/j.pain.0000000000002492
关键词
NGF; TrkA; Mechanical allodynia; Bone resorption; Arthritis
资金
- Conseil Regional Auvergne-Rhone-Alpes (project: Ressourcement S3, Arth-Innov) Inserm
- Feder
- French government IDEX-ISITE initiative [16-IDEX-0001 (CAP 20-25)]
- France Genomique National infrastructure [ANR-10-INBS-09]
Our study using knock-in TrkA/C mice reveals that the TrkA-specific intracellular signaling pathways play a crucial role in mechanical hypersensitivity and bone alterations in rheumatoid arthritis.
Rheumatoid arthritis is frequently associated with chronic pain that still remains difficult to treat. Targeting nerve growth factor (NGF) seems very effective to reduce pain in at least osteoarthritis and chronic low back pain but leads to some potential adverse events. Our aim was to better understand the involvement of the intracellular signalling pathways activated by NGF through its specific tyrosine kinase type A (TrkA) receptor in the pathophysiology of rheumatoid arthritis using the complete Freund adjuvant model in our knock-in TrkA/C mice. Our multimodal study demonstrated that knock-in TrkA/C mice exhibited a specific decrease of mechanical allodynia, weight-bearing deficit, peptidergic (CGRP+) and sympathetic (TH+) peripheral nerve sprouting in the joints, a reduction in osteoclast activity and bone resorption markers, and a decrease of CD68-positive cells in the joint with no apparent changes in joint inflammation compared with wild-type mice after arthritis. Finally, transcriptomic analysis shows several differences in dorsal root ganglion mRNA expression of putative mechanotransducers, such as acid-sensing ionic channel 3 and TWIK-related arachidonic acid activated K+ channel, as well as intracellular pathways, such as c-Jun, in the joint or dorsal root ganglia. These results suggest that TrkA-specific intracellular signalling pathways are specifically involved in mechanical hypersensitivity and bone alterations after arthritis using TrkA/C mice.
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