POS0404 SOLUBLE LOW AFFINITY NERVE GROWTH FACTOR RECEPTOR (LNGFR) MAY REGULATE PAIN IN KNEE OSTEOARTHRITIS

• Published in: Annals of the rheumatic diseases Vol. 82; no. Suppl 1; pp. 457 - 458
• Main Authors: Altaie, A., Campbell, M., Doyle, R., Owston, H., Jones, E., Feibel, R., Westbrook, S., Mcgonagle, D.
• Format: Journal Article
• Language: English
• Published: Kidlington BMJ Publishing Group Ltd and European League Against Rheumatism 01.06.2023; Elsevier B.V; Elsevier Limited
• Subjects: Affinity; Arthritis; Biomarkers; Brain-derived neurotrophic factor; Clinical trials; Cytokines; Growth factors; Inflammation; Knee; Nerve growth factor; Neurotrophin 3; Osteoarthritis; Pain; Rheumatology; Scientific Abstracts; Statistical analysis; Statistics; Synovial fluid; TrkA protein; TrkA receptors; Tropomyosin; Tumor necrosis factor receptors; Tumor necrosis factor-TNF; Tumor necrosis factor-α; United Kingdom > UK; Biomarkers; Osteoarthritis; Pain
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2023-eular.3522

BackgroundOsteoarthritis (OA) is a disease of the entire joint. OA causes significant pain that has been linked to increased neurotrophin concentrations, including mature nerve growth factor β-NGF[2]. β-NGF antagonism was efficacious in reducing OA pain in clinical trials but was associated with rapidly progressive OA[1], hampering mainstream delivery of this treatment. β-NGF binds to tropomyosin receptor kinase A (TrkA) and low-affinity NGF receptor (LNGFR), a tumour necrosis factor receptor (TNFR) superfamily member. Given that TNFR superfamily member shedding regulates inflammation and immunity, soluble LNGFR (sLNGFR) shedding might be important in pain regulation[3] and association between these molecules and OA-related knee pain may point to an alternative, less harmful approach to β-NGF antagonism and pain reduction.ObjectivesTherefore, we investigated the association between (synovial fluid) SF levels of soluble LNGFR, TrkA, proNGF and NGF and other relevant neurotrophins with OA-related knee pain. Key cytokines involved in TNFR family receptor shedding were also investigated.MethodsSF was procured from 42 subjects with severe OA at the time of arthroplasty. VAS pain scores were recorded pre-operatively. In-house developed ELISAs, commercial ELISAs and LEGENDplex™ were used to measure sLNGFR, TrkA, proNGF, β–NGF, other neurotrophins and cytokines including TNF-α. Statistical analysis was implemented using Graphpad Prism software, version 9.0. Data normality was analysed using Kolmogorov-Smirnov and Shapiro-Wilk testing. The Spearman rank correlation test and multivariate linear regression analyses were performed to assess the correlations. Statistical significance was defined as p<0.05.ResultsVAS pain score positively correlated with β–NGF (r=0.34, p<0.05) and TrkA (r=0.33, p<0.05, r=0.32, p>0.05). There was a positive association trend with NT-3 and BDNF with a negative trend for ProNGF. sLNGFR. The β–NGF/TrkA ratio showed a strong positive correlation with VAS (r=0.80, p<0.001). However, there was no correlation between pain and the β–NGF/sLNGFR ratio (r=-0.08, p>0.05). TNF-α positively correlated with β–NGF (r= 0.83, p<0.001), NT-3 (r= 0.66, p<0.01), and BDNF (r= 0.50, p<0.05) and negatively with ProNGF (r= -0.74, p<0.01). Additionally, TNF-α positively correlated with TrkA (r=0.62, p>0.05) and sLNGFR (r=0.26, p>0.05).ConclusionOur results align well with the previously-proposed β–NGF pain molecular pathway and suggest that inflammation-related endogenous cleavage of sLNGFR, but not TrkA may modulate pain in vivo in OA as sLNGFR act as sink of the endogenous NGF. These novel findings may provide new avenues for safe and effective pain reduction strategies in OA.References[1](2017), 110–18[2]Walsh, D. A., D. F. McWilliams, M. J. Turley, M. R. Dixon, R. E. Fransès, P. I. Mapp, and D. Wilson, Rheumatology (Oxford), 49. 10 (2010), 1852-61[3]Weskamp, G., J. Schlöndorff, L. Lum, J. D. Becherer, T. W. Kim, P. Saftig, D. Hartmann, G. Murphy, and C. P. Blobel, ‘, J Biol Chem, 279. 6 (2004), 4241-9Figure 1.Correlation matrix between pain score and neurotrophins and neurotrophins receptors all depicted as a heat map.Acknowledgements:NIL.Disclosure of InterestsAla Altaie: None declared, Mark Campbell: None declared, Rachel Doyle Employee of: work for Levicept Ltd, Discovery Park, Sandwich, United Kingdom, Heather Owston: None declared, Elena Jones: None declared, Robert Feibel: None declared, Simon Westbrook Shareholder of: Levicept Ltd, Discovery Park, Sandwich, United Kingdom, Dennis McGonagle: None declared.