Abstract
SummaryObjectiveNerve growth factor (NGF) has a pivotal role in peripheral hyperalgesia and inflammation; anti-NGF antibodies attenuate pain responses in inflammatory pain models, and in people with osteoarthritis (OA) or low back pain. The aim of this study was to characterise the peripheral mechanisms contributing to the analgesic effects of anti-NGF antibody treatment in an established model of joint pain, which mimics key clinical features of OA.DesignEffects of preventative vs therapeutic treatment with an anti-NGF antibody (monoclonal antibody 911: muMab 911 (10 mg/kg, s.c.)) on pain behaviour (weight bearing asymmetry and hindpaw withdrawal thresholds (PWT)), cartilage damage, synovitis and numbers of subchondral osteoclasts were investigated in the monosodium iodoacetate (MIA) model. Potential direct effects of NGF on receptor activator of nuclear factor kappa-B ligand (RANKL) mediated osteoclastogenesis were investigated in cultured human osteoclasts.ResultsIntra-articular MIA injection resulted in significant pain behaviour, cartilage damage, synovitis and increased numbers of subchondral osteoclasts. Both preventative and therapeutic treatment with muMab 911 significantly prevented, or reversed, MIA-induced pain behaviour, but did not alter cartilage or synovial pathology quantified at the end of the treatment period. NGF did not facilitate RANKL driven osteoclast differentiation in vitro, but preventative or therapeutic muMab 911 reduced numbers of TRAP positive osteoclasts in the subchondral bone.ConclusionsWe demonstrate that anti-NGF antibody treatment attenuates OA pain behaviour despite permitting cartilage damage and synovitis. Indirect effects on subchondral bone remodelling may contribute to the analgesic effects of NGF blockade.
Highlights
Osteoarthritis (OA) is the most common form of arthritis and the fastest growing chronic pain disease worldwide[1], prevalence of OA increases with age[2]
Animal and model induction and joint pathology up to day 28; effect of therapeutic treatment vs vehicle on pain behaviour and joint pathology up to day 28; effect of a preventative treatment of IgG1 vs vehicle on pain behaviour up to day 28 evaluation of joint pathology at day 14 in monosodium iodoacetate (MIA) and saline control rats
Intra-articular injection of MIA was associated with a significant increase in weight bearing asymmetry and a significant decrease in ipsilateral hindpaw withdrawal thresholds, compared to intraarticular injection of saline [Fig. 1(A), (C)]
Summary
Osteoarthritis (OA) is the most common form of arthritis and the fastest growing chronic pain disease worldwide[1], prevalence of OA increases with age[2]. All compartments of OA joints undergo structural changes, which impacts upon function, causing disability and reducing quality of life[2]. Joint structural changes associated with OA pain include synovitis[3] and bone marrow lesions[4]. OA pain is characterised by both pain on loading and spread of pain to sites remote from the diseased joint, and clinical evidence supports a contribution of both peripheral and central sensitization mechanisms to OA pain[5]. Rodent models which mimic aspects of the clinical pathology and exhibit pain on loading (weight bearing) and lowering of paw withdrawal thresholds (PWT) at remote sites[6] play a pivotal role in elucidating mechanisms of OA pain, which cannot be readily interrogated in clinical studies
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