Local ASIC3 modulates pain and disease progression in a rat model of osteoarthritis.
BACKGROUND
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.


METHODS
We 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.


RESULTS
OA 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.


CONCLUSIONS
Local 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.
Department of Orthopaedic Surgery, Kochi University, Oko-cho Kohasu, Nankoku 783-8505, Japan. ikeuchim@kochi-u.ac.jp
Masashi
M
Izumi
Masahiko
M
Ikeuchi
Qinghui
Q
Ji
Toshikazu
T
Tani
D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003064:Cnidarian Venoms / Q000008:administration & dosage / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D019807:Iodoacetic Acid / Q000633:toxicity; D007719:Knee Joint / Q000294:innervation / Q000503:physiopathology; D008297:Male; D010003:Osteoarthritis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D010146:Pain / Q000139:chemically induced / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
C501880:APETx2 protein, Anthopleura elegantissima; C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D003064:Cnidarian Venoms; D019807:Iodoacetic Acid