title: Treatment of murine osteoarthritis with TrkAd5 reveals a pivotal role for nerve growth factor in non-inflammatory joint pain.
abstract: The origin of pain in osteoarthritis is poorly understood, but it is generally thought to arise from inflammation within the innervated structures of the joint, such as the synovium, capsule and bone. We investigated the role of nerve growth factor (NGF) in pain development in murine OA, and the analgesic efficacy of the soluble NGF receptor, TrkAD5. OA was induced in mice by destabilisation of the medial meniscus and pain was assessed by measuring hind-limb weight distribution. RNA was extracted from joints, and NGF and TNF expressions were quantified. The effect of tumour necrosis factor (TNF) and neutrophil blockade on NGF expression and pain were also assessed. NGF was induced in the joints during both post-operative (day 3) and OA (16weeks) pain, but not in the non-painful stage of disease (8weeks post-surgery). TrkAd5 was highly effective at suppressing pain in both phases. Induction of NGF in the post-operative phase of pain was TNF-dependent as anti-TNF reduced NGF expression in the joint and abrogated pain. However, TNF was not regulated in the late OA joints, and pain was not affected by anti-TNF therapy. Fucoidan, by suppressing cellular infiltration into the joint, was able to suppress post-operative, but not late OA pain. These results indicate that NGF is an important mediator of OA pain and that TrkAd5 represents a potent novel analgesic in this condition. They also suggest that, unlike post-operative pain, induction of pain in OA may not necessarily be driven by classical inflammatory processes.
authors.affiliation: Kennedy Institute of Rheumatology, Imperial College London, London W6 8LH, UK Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Dorothy Hodgkin Building, Whitson St, University of Bristol, Bristol BS1 3NY, UK School of Veterinary and Biomedical Sciences, Murdoch University, Perth, Western Australia 6015, Australia.
authors.forename: Kay E
authors.initials: KE
authors.lastname: McNamee
authors.forename: Annika
authors.initials: A
authors.lastname: Burleigh
authors.forename: Luke L
authors.initials: LL
authors.lastname: Gompels
authors.forename: Marc
authors.initials: M
authors.lastname: Feldmann
authors.forename: Shelley J
authors.initials: SJ
authors.lastname: Allen
authors.forename: Richard O
authors.initials: RO
authors.lastname: Williams
authors.forename: David
authors.initials: D
authors.lastname: Dawbarn
authors.forename: Tonia L
authors.initials: TL
authors.lastname: Vincent
authors.forename: Julia J
authors.initials: JJ
authors.lastname: Inglis
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D018771:Arthralgia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D000068800:Etanercept; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use; D007719:Knee Joint / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000819:agonists* / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010147:Pain Measurement / Q000379:methods; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011134:Polysaccharides / Q000494:pharmacology; D020917:Receptor, trkA / Q000627:therapeutic use*; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000700:Analgesics; D007074:Immunoglobulin G; D010446:Peptide Fragments; D010455:Peptides; D011134:Polysaccharides; D018124:Receptors, Tumor Necrosis Factor; C551301:TrkAd5 peptide; D014409:Tumor Necrosis Factor-alpha; D020932:Nerve Growth Factor; C007789:fucoidan; D020917:Receptor, trkA; D000068800:Etanercept