Nociceptive tolerance is improved by bradykinin receptor B1 antagonism and joint morphology is protected by both endothelin type A and bradykinin receptor B1 antagonism in a surgical model of osteoarthritis
1 Orthopaedic Molecular Biology Laboratory, Sainte-Justine Hospital Research Centre, 3175 Côte Sainte-Catherine, Montreal, QC, H3T 1C5, Canada
2 Paediatric Mechanobiology Laboratory, Sainte-Justine Hospital Research Centre, 3175 Côte Sainte-Catherine, Montreal, QC, H3T 1C5, Canada
3 IPS Thérapeutique, 3201 Jean-Mignault, Sherbrooke, QC, J1E 4K8, Canada
4 Faculty of Dentistry, Université de Montréal, PO Box 6128 Stn CV, Montreal, QC, H3C 3J7, Canada
Arthritis Research & Therapy 2011, 13:R76 doi:10.1186/ar3338Published: 16 May 2011
Endothelin-1, a vasoconstrictor peptide, influences cartilage metabolism mainly via endothelin receptor type A (ETA). Along with the inflammatory nonapeptide vasodilator bradykinin (BK), which acts via bradykinin receptor B1 (BKB1) in chronic inflammatory conditions, these vasoactive factors potentiate joint pain and inflammation. We describe a preclinical study of the efficacy of treatment of surgically induced osteoarthritis with ETA and/or BKB1 specific peptide antagonists. We hypothesize that antagonism of both receptors will diminish osteoarthritis progress and articular nociception in a synergistic manner.
Osteoarthritis was surgically induced in male rats by transection of the right anterior cruciate ligament. Animals were subsequently treated with weekly intra-articular injections of specific peptide antagonists of ETA and/or BKB1. Hind limb nociception was measured by static weight bearing biweekly for two months post-operatively. Post-mortem, right knee joints were analyzed radiologically by X-ray and magnetic resonance, and histologically by the OARSI histopathology assessment system.
Single local BKB1 antagonist treatment diminished overall hind limb nociception, and accelerated post-operative recovery after disease induction. Both ETA and/or BKB1 antagonist treatments protected joint radiomorphology and histomorphology. Dual ETA/BKB1 antagonism was slightly more protective, as measured by radiology and histology.
BKB1 antagonism improves nociceptive tolerance, and both ETA and/or BKB1 antagonism prevents joint cartilage degradation in a surgical model of osteoarthritis. Therefore, they represent a novel therapeutic strategy: specific receptor antagonism may prove beneficial in disease management.