Background/Purpose

Levels of endogenous nerve growth factor (NGF) are increased in osteoarthritic (OA) joints in patients and animal models and may be an important cause of pain associated with OA. NGF binds to the high-affinity tropomyosin kinase A (Trk A) and low affinity p75 receptors. Analgesic benefits of the humanized antibody tanezumab in clinical trials have encouraged development of NGF blockade as a novel analgesic strategy for OA, although rare and currently unexplained adverse effects on joint structure have been a concern. Blocking antibodies against NGF inhibit signalling through both Trk A and p75. The ability of selective inhibitors of Trk A tyrosine kinase activity to inhibit OA pain has not previously been reported. We investigated the effect of a selective Trk A inhibitor on pain behaviour, synovial inflammation and joint structure in a chemically induced monosodium iodoacetate (MIA) model and a surgically induced medial meniscal transection (MNX) model of OA.

Methods

Male Sprague Dawley rats (n=10/group, 200-300g) were briefly anaesthetised and given a single intra-articular injection of (1mg/50µl) MIA or saline or underwent MNX or SHAM surgery. The development of pain behaviour was assessed using weight bearing asymmetry (difference in hind limb weight bearing (%)). Two weeks after OA induction, rats were stratified according to their pain responses and received a selective Trk A inhibitor (AR00475786) or vehicle for the remainder of the study. Alterations in knee structure and inflammation were examined by macroscopic visualisation of articular surfaces (Guingamp classification) and histology. Differences between groups were analysed using Kruskal Wallis test followed by post hoc Dunn’s test and presented as mean (95% confidence interval).

Results

Rats receiving intra-articular injection of MIA or that underwent MNX surgery developed significant increases in %weight-bearing asymmetry (saline v MIA; day 3 = 2.9 [-4.7 – 11] v 36 [22-51], day 7 = 3.3 [-3 – 9.6] v 24 [14-35] *p<0.05, SHAM v MNX; day 3 = 11.5 [-0.78 – 3.9] v 20 [9.3-31], day 7 = 1.4 [-0.83 – 3.7] v 18 [9.4-26] *p<0.05) with significant increases in synovial inflammation (saline v MIA; 0.78 [0.14-1.4] v 2.3 [2-2.6] **p<0.01). Following drug treatment with AR00475786, there was a significant reversal of %weight-bearing asymmetry (MIA + Vehicle v MIA + drug; day 21 = 27 [21-23] v 3.7 [-1.4 – 8.8] **p<0.01, MNX + Vehicle v MNX + drug; day 21 = 27 [21-32] v 4.8 [1.1-8.6] **p<0.01) and reduced synovial inflammation (MIA + Vehicle v MIA + drug; day21 =  2.3 [2-2.6] v 1.2 [0.32-2.1] *p<0.05). Administration of the Trk A inhibitor did not significantly affect macroscopic chondropathy.

Conclusion

NGF may mediate pain behaviour in rats with MIA or MNX-induced OA through diverse mechanisms. Reductions in weight bearing asymmetry suggest effects of blockade of endogenous NGF activity through Trk A inhibition on peripheral pain processing. Reductions in synovitis suggest additional analgesic mechanisms of NGF inhibition. Trk A inhibition has therapeutic potential in the treatment of OA. Better understanding of the contributions of NGF to OA pathology may help realise the potential of NGF inhibition for OA treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effects-of-anti-ngf-strategies-in-two-animal-models-of-osteoarthritis-oa/