Abstract
BackgroundRecent data have suggested a relationship between acute arthritic pain and acid sensing ion channel 3 (ASIC3) on primary afferent fibers innervating joints. The purpose of this study was to clarify the role of ASIC3 in a rat model of osteoarthritis (OA) which is considered a degenerative rather than an inflammatory disease.MethodsWe induced OA via intra-articular mono-iodoacetate (MIA) injection, and evaluated pain-related behaviors including weight bearing measured with an incapacitance tester and paw withdrawal threshold in a von Frey hair test, histology of affected knee joint, and immunohistochemistry of knee joint afferents. We also assessed the effect of ASIC3 selective peptide blocker (APETx2) on pain behavior, disease progression, and ASIC3 expression in knee joint afferents.ResultsOA rats showed not only weight-bearing pain but also mechanical hyperalgesia outside the knee joint (secondary hyperalgesia). ASIC3 expression in knee joint afferents was significantly upregulated approximately twofold at Day 14. Continuous intra-articular injections of APETx2 inhibited weight distribution asymmetry and secondary hyperalgesia by attenuating ASIC3 upregulation in knee joint afferents. Histology of ipsilateral knee joint showed APETx2 worked chondroprotectively if administered in the early, but not late phase.ConclusionsLocal ASIC3 immunoreactive nerve is strongly associated with weight-bearing pain and secondary hyperalgesia in MIA-induced OA model. APETx2 inhibited ASIC3 upregulation in knee joint afferents regardless of the time-point of administration. Furthermore, early administration of APETx2 prevented cartilage damage. APETx2 is a novel, promising drug for OA by relieving pain and inhibiting disease progression.
Highlights
Recent data have suggested a relationship between acute arthritic pain and acid sensing ion channel 3 (ASIC3) on primary afferent fibers innervating joints
Our previous reports showed that secondary hyperalgesia following carrageenan-induced arthritis does not develop in ASIC3 knockout mice while primary mechanical hyperalgesia develops between knockout and wildtype mice
ASIC3 immunoreactive peripheral nerves were upregulated in inflamed synovium of the knee joint and dosal root ganglia (DRG) along with calcitonin gene-related peptide (CGRP) [16,17]
Summary
Recent data have suggested a relationship between acute arthritic pain and acid sensing ion channel 3 (ASIC3) on primary afferent fibers innervating joints. The purpose of this study was to clarify the role of ASIC3 in a rat model of osteoarthritis (OA) which is considered a degenerative rather than an inflammatory disease. There has been considerable evidence suggesting that ASIC3 plays a significant role in joint inflammatory pain [13,14,15]. Our previous reports showed that secondary hyperalgesia following carrageenan-induced arthritis (response to von-Frey filaments applied to the paw) does not develop in ASIC3 knockout mice while primary mechanical hyperalgesia (response to tweezer applied to the inflamed knee joint) develops between knockout and wildtype mice. There has been no evidence yet for the relationship between ASIC3 and OA, which is considered a degenerative rather than an inflammatory disease
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