Liraglutide, a glucagon-like peptide 1 receptor agonist, exerts analgesic, anti-inflammatory and anti-degradative actions in osteoarthritis
C Meurot, C Martin, L Sudre, J Breton, C Bougault, R Rattenbach, K Bismuth, C Jacques, F Berenbaum, C Meurot, C Martin, L Sudre, J Breton, C Bougault, R Rattenbach, K Bismuth, C Jacques, F Berenbaum
Abstract
Osteoarthritis (OA) is a common disabling disease worldwide, with no effective and safe disease-modifying drugs (DMOAD) in the market. However, studies suggest that drugs, such as liraglutide, which possess strong potential in decreasing low-grade systemic inflammation may be effective in treating OA. Therefore, the aim of this study was to examine the anti-inflammatory, analgesic, and anti-degradative effects in OA using in vitro and in vivo experiments. The results showed that intra-articular injection of liraglutide alleviated pain-related behavior in in vivo sodium monoiodoacetate OA mouse model, which was probably driven by the GLP-1R-mediated anti-inflammatory activity of liraglutide. Moreover, liraglutide treatment significantly decreased IL-6, PGE2 and nitric oxide secretion, and the expression of inflammatory genes in vitro in chondrocytes and macrophages in a dose-dependent manner. Additionally, liraglutide shifted polarized macrophage phenotype in vitro from the pro-inflammatory M1 phenotype to the M2 anti-inflammatory phenotype. Furthermore, liraglutide exerted anti-catabolic activity by significantly decreasing the activities of metalloproteinases and aggrecanases, a family of catabolic enzymes involved in cartilage breakdown in vitro. Overall, the findings of this study showed that liraglutide ameliorated OA-associated pain, possess anti-inflammatory and analgesic properties, and could constitute a novel therapeutic candidate for OA treatment.
Conflict of interest statement
Dr. Berenbaum reports personal fees from AstraZeneca, Boehringer, Bone Therapeutics, CellProthera, Expanscience, Galapagos, Gilead, Grunenthal, GSK, Eli Lilly, Merck Sereno, MSD, Nordic Pharma, Nordic Bioscience, Novartis, Pfizer, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, 4P Pharma, grants from TRB Chemedica; In addition. Dr Berenbaum is the CEO of 4Moving Biotech and chair of the scientific advisory board of 4P Pharma. Dr. Rattenbach is the CEO of 4P Pharma and the chairwoman of 4Moving Biotech. 4Moving Biotech and Sorbonne University own 2 patents for method of use of GLP1 analogs in the treatment of osteoarthritis (PCT/FR2013/051998 and PCT/IB2018//059100).
© 2022. The Author(s).
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References
- Robinson WH, et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 2016;12:580–592. doi: 10.1038/nrrheum.2016.136.
- Palazzo C, Ravaud JF, Papelard A, Ravaud P, Poiraudeau S. The burden of musculoskeletal conditions. PLoS ONE. 2014;9:e90633. doi: 10.1371/journal.pone.0090633.
- James SL, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1789–1858. doi: 10.1016/S0140-6736(18)32279-7.
- Gupta S, Hawker GA, Laporte A, Croxford R, Coyte PC. The economic burden of disabling hip and knee osteoarthritis (OA) from the perspective of individuals living with this condition. Rheumatology (Oxford) 2005;44:1531–1537. doi: 10.1093/rheumatology/kei049.
- Osteoarthritis: Structural Endpoints for the Development of Drugs, Devices, and Biological Products for Treatment Guidance for Industry, 6 (2018).
- Oo WM, Little C, Duong V, Hunter DJ. The development of disease-modifying therapies for osteoarthritis (DMOADs): The evidence to date. Drug Des. Dev. Ther. 2021;15:2921–2945. doi: 10.2147/DDDT.S295224.
- Little CB, Hunter DJ. Post-traumatic osteoarthritis: From mouse models to clinical trials. Nat. Rev. Rheumatol. 2013;9:485–497. doi: 10.1038/nrrheum.2013.72.
- Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat. Rev. Rheumatol. 2010;6:625–635. doi: 10.1038/nrrheum.2010.159.
- Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: A disease of the joint as an organ. Arthritis Rheum. 2012;64:1697–1707. doi: 10.1002/art.34453.
- Hunter DJ. Pharmacologic therapy for osteoarthritis—The era of disease modification. Nat. Rev. Rheumatol. 2011;7:13–22. doi: 10.1038/nrrheum.2010.178.
- Bondeson J, et al. The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis Rheum. 2010;62:647–657. doi: 10.1002/art.27290.
- Manferdini C, et al. Adipose stromal cells mediated switching of the pro-inflammatory profile of M1-like macrophages is facilitated by PGE2: In vitro evaluation. Osteoarthr. Cartil. 2017;25:1161–1171. doi: 10.1016/j.joca.2017.01.011,Pubmed:28153787.
- Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!) Osteoarthr. Cartil. 2013;21:16–21. doi: 10.1016/j.joca.2012.11.012.
- Oren TW, Botolin S, Williams A, Bucknell A, King KB. Arthroplasty in veterans: Analysis of cartilage, bone, serum, and synovial fluid reveals differences and similarities in osteoarthritis with and without comorbid diabetes. J. Rehabil. Res. Dev. 2011;48:1195–1210. doi: 10.1682/jrrd.2010.09.0186.
- Nah SS, et al. Effects of advanced glycation end products on the expression of COX-2, PGE2 and NO in human osteoarthritic chondrocytes. Rheumatology (Oxford) 2008;47:425–431. doi: 10.1093/rheumatology/kem376.
- Laiguillon MC, et al. Characterization of diabetic osteoarthritic cartilage and role of high glucose environment on chondrocyte activation: Toward pathophysiological delineation of diabetes mellitus-related osteoarthritis. Osteoarthr. Cartil. 2015;23:1513–1522. doi: 10.1016/j.joca.2015.04.026.
- Courties A, Berenbaum F, Sellam J. The phenotypic approach to osteoarthritis: A look at metabolic syndrome-associated osteoarthritis. Joint Bone Spine. 2019;86:725–730. doi: 10.1016/j.jbspin.2018.12.005.
- Lee H, et al. TissueGene-C promotes an anti-inflammatory micro-environment in a rat monoiodoacetate model of osteoarthritis via polarization of M2 macrophages leading to pain relief and structural improvement. Inflammopharmacology. 2020;28:1237–1252. doi: 10.1007/s10787-020-00738-y.
- Iwai T, Ito S, Tanimitsu K, Udagawa S, Oka J-I. Glucagon-like peptide-1 inhibits LPS-induced IL-1β production in cultured rat astrocytes. Neurosci. Res. 2006;55:352–360. doi: 10.1016/j.neures.2006.04.008.
- Andersen A, Lund A, Knop FK, Vilsbøll T. Glucagon-like peptide 1 in health and disease. Nat. Rev. Endocrinol. 2018;14:390–403. doi: 10.1038/s41574-018-0016-2.
- Orskov C, Wettergren A, Holst JJ. Biological effects and metabolic rates of glucagonlike peptide-1 7–36 amide and glucagonlike peptide-1 7–37 in healthy subjects are indistinguishable. Diabetes. 1993;42:658–661. doi: 10.2337/diab.42.5.658.
- Lee YS, et al. Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes. Diabetologia. 2012;55:2456–2468. doi: 10.1007/s00125-012-2592-3.
- Dobrian AD, et al. Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice. Am. J. Physiol. Endocrinol. Metab. 2011;300:E410–E421. doi: 10.1152/ajpendo.00463.2010.
- Parthsarathy V, Hölscher C. The type 2 diabetes drug liraglutide reduces chronic inflammation induced by irradiation in the mouse brain. Eur. J. Pharmacol. 2013;700:42–50. doi: 10.1016/j.ejphar.2012.12.012.
- Berenbaum, F et al. EP2890390—Treatment of Osteoarthritis WITH Incretin Hormones or Analogues Thereof (2014).
- Krenn V, et al. Synovitis score: Discrimination between chronic low-grade and high-grade synovitis. Histopathology. 2006;49:358–364. doi: 10.1111/j.1365-2559.2006.02508.x.
- Cha Y, et al. Drug repurposing from the perspective of pharmaceutical companies. Br. J. Pharmacol. 2018;175:168–180. doi: 10.1111/bph.13798.
- Pushpakom S, et al. Drug repurposing: Progress, challenges and recommendations. Nat. Rev. Drug Discov. 2019;18:41–58. doi: 10.1038/nrd.2018.168.
- Schisano B, et al. GLP-1 analogue, liraglutide protects human umbilical vein endothelial cells against high glucose induced endoplasmic reticulum stress. Regul. Pept. 2012;174:46–52. doi: 10.1016/j.regpep.2011.11.008.
- Hansen HH, et al. The GLP-1 receptor agonist liraglutide improves memory function and increases hippocampal CA1 neuronal numbers in a senescence-accelerated mouse model of Alzheimer’s disease. J. Alzheimers Dis. 2015;46:877–888. doi: 10.3233/JAD-143090.
- Körner M, Stöckli M, Waser B, Reubi JC. GLP-1 receptor expression in human tumors and human normal tissues: Potential for in vivo targeting. J. Nucl. Med. 2007;48:736–743. doi: 10.2967/jnumed.106.038679.
- Amato A, Baldassano S, Liotta R, Serio R, Mulè F. Exogenous glucagon-like peptide 1 reduces contractions in human colon circular muscle. J. Endocrinol. 2014;221:29–37. doi: 10.1530/JOE-13-0525.
- Bang-Berthelsen CH, et al. GLP-1 induces barrier protective expression in Brunner’s glands and regulates colonic inflammation. Inflamm. Bowel Dis. 2016;22:2078–2097. doi: 10.1097/MIB.0000000000000847.
- Amato A, et al. Peripheral motor action of glucagon-like peptide-1 through enteric neuronal receptors. Neurogastroenterol. Motil. 2010;22:664. doi: 10.1111/j.1365-2982.2010.01476.x.
- Chen J, et al. Glucagon-like peptide-1 receptor regulates endoplasmic reticulum stress-induced apoptosis and the associated inflammatory response in chondrocytes and the progression of osteoarthritis in rat. Cell Death Dis. 2018;9:212. doi: 10.1038/s41419-017-0217-y.
- Andersen DB, et al. Using a reporter mouse to map known and novel sites of GLP-1 receptor expression in peripheral tissues of male mice. Endocrinology. 2021;162:246. doi: 10.1210/endocr/bqaa246.
- Que Q, et al. The GLP-1 agonist, liraglutide, ameliorates inflammation through the activation of the PKA/CREB pathway in a rat model of knee osteoarthritis. J. Inflamm. (Lond.) 2019;16:13. doi: 10.1186/s12950-019-0218-y.
- Bedson J, Croft PR. The discordance between clinical and radiographic knee osteoarthritis: A systematic search and summary of the literature. BMC Musculoskelet. Disord. 2008;9:116. doi: 10.1186/1471-2474-9-116.
- Malfait AM, Schnitzer TJ. Towards a mechanism-based approach to pain management in osteoarthritis. Nat. Rev. Rheumatol. 2013;9:654–664. doi: 10.1038/nrrheum.2013.138.
- Anand U, et al. Glucagon-like peptide 1 receptor (GLP-1R) expression by nerve fibres in inflammatory bowel disease and functional effects in cultured neurons. PLoS ONE. 2018;13:e0198024. doi: 10.1371/journal.pone.0198024.
- Chakrabarti S, Jadon DR, Bulmer DC, Smith ESJ. Human osteoarthritic synovial fluid increases excitability of mouse dorsal root ganglion sensory neurons: An in-vitro translational model to study arthritic pain. Rheumatology (Oxford) 2020;59:662–667. doi: 10.1093/rheumatology/kez331.
- Pitcher T, Sousa-Valente J, Malcangio M. The monoiodoacetate model of osteoarthritis pain in the mouse. J. Vis. Exp. 2016;111:53746. doi: 10.3791/53746.
- Conaghan PG, Cook AD, Hamilton JA, Tak PP. Therapeutic options for targeting inflammatory osteoarthritis pain. Nat. Rev. Rheumatol. 2019;15:355–363. doi: 10.1038/s41584-019-0221-y.
- Gudbergsen H, et al. Liraglutide after diet-induced weight loss for pain and weight control in knee osteoarthritis: A randomized controlled trial. Am. J. Clin. Nutr. 2021;113:314–323. doi: 10.1093/ajcn/nqaa328.
- Syx D, Tran PB, Miller RE, Malfait AM. Peripheral mechanisms contributing to osteoarthritis pain. Curr. Rheumatol. Rep. 2018;20:9. doi: 10.1007/s11926-018-0716-6.
- Neogi T, et al. Association of joint inflammation with pain sensitization in knee osteoarthritis: The multicenter osteoarthritis study. Arthritis Rheumatol. 2016;68:654–661. doi: 10.1002/art.39488.
- Richter F, et al. Tumor necrosis factor causes persistent sensitization of joint nociceptors to mechanical stimuli in rats. Arthritis Rheum. 2010;62:3806–3814. doi: 10.1002/art.27715.
- Ambarus CA, et al. Systematic validation of specific phenotypic markers for in vitro polarized human macrophages. J. Immunol. Methods. 2012;375:196–206. doi: 10.1016/j.jim.2011.10.013.
- Liu B, Zhang M, Zhao J, Zheng M, Yang H. Imbalance of M1/M2 macrophages is linked to severity level of knee osteoarthritis. Exp. Ther. Med. 2018;16:5009–5014. doi: 10.3892/etm.2018.6852.
- Wood MJ, et al. Macrophage proliferation distinguishes 2 subgroups of knee osteoarthritis patients. JCI Insight. 2019 doi: 10.1172/jci.insight.125325.
- Sawada N, et al. Glucagon-like peptide-1 receptor agonist liraglutide ameliorates the development of periodontitis. J. Diabetes Res. 2020;2020:8843310. doi: 10.1155/2020/8843310.
- Wan S, Sun H. Glucagon-like peptide-1 modulates RAW264.7 macrophage polarization by interfering with the JNK/STAT3 signaling pathway. Exp. Ther. Med. 2019;17:3573–3579. doi: 10.3892/etm.2019.7347.
- Ban K, et al. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation. 2008;117:2340–2350. doi: 10.1161/CIRCULATIONAHA.107.739938.
- Ossum A, van Deurs U, Engstrøm T, Jensen JS, Treiman M. The cardioprotective and inotropic components of the postconditioning effects of GLP-1 and GLP-1(9–36)a in an isolated rat heart. Pharmacol. Res. 2009;60:411–417. doi: 10.1016/j.phrs.2009.06.004.
- Mueller MB, Tuan RS. Anabolic/catabolic balance in pathogenesis of osteoarthritis: Identifying molecular targets. PM R. 2011;3(Supplement 1):S3–S11. doi: 10.1016/j.pmrj.2011.05.009.
- Glasson SS, Blanchet TJ, Morris EA. The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthr. Cartil. 2007;15:1061–1069. doi: 10.1016/j.joca.2007.03.006.
- Baudart P, Louati K, Marcelli C, Berenbaum F, Sellam J. Association between osteoarthritis and dyslipidaemia: A systematic literature review and meta-analysis. RMD Open. 2017;3:e000442. doi: 10.1136/rmdopen-2017-000442.
- Yanai Effects of liraglutide, a human glucagon-like peptide-1 analog, on glucose/lipid metabolism, and adipocytokines in patients with Type 2 diabetes. J. J. Endocrinol. Metab. 2011 doi: 10.4021/jem38w.
- Adams JD. Pain and inflammation. Curr. Med. Chem. 2020;27:1444–1445. doi: 10.2174/092986732709200327092413.
- Ghouri A, Conaghan PG. Update on novel pharmacological therapies for osteoarthritis. Ther. Adv. Musculoskelet. 2019;11:X1986449.
- Eckstein F, et al. Intra-articular sprifermin reduces cartilage loss in addition to increasing cartilage gain independent of location in the femorotibial joint: Post-hoc analysis of a randomised, placebo-controlled phase II clinical trial. Ann. Rheum. Dis. 2020;79:525–528. doi: 10.1136/annrheumdis-2019-216453.
- Deshmukh V, et al. A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee. Osteoarthr. Cartil. 2018;26:18–27. doi: 10.1016/j.joca.2017.08.015.
- Yazici Y, et al. Lorecivivint, a novel intraarticular CDC-like kinase 2 and dual-specificity tyrosine phosphorylation-regulated kinase 1A inhibitor and Wnt pathway modulator for the treatment of knee osteoarthritis: A phase II randomized trial. Arthritis Rheumatol. 2020;72:1694–1706. doi: 10.1002/art.41315.
- Grässel S, Muschter D. Recent advances in the treatment of osteoarthritis. F1000Res. 2020;9:325. doi: 10.12688/f1000research.22115.1.
- Mankin HJ. Biochemical and metabolic aspects of osteoarthritis. Orthop. Clin. N. Am. 1971;2:19–31. doi: 10.1016/S0030-5898(20)31137-8.
- Courties A, et al. Clearing method for 3-dimensional immunofluorescence of osteoarthritic subchondral human bone reveals peripheral cholinergic nerves. Sci. Rep. 2020;10:8852. doi: 10.1038/s41598-020-65873-6.
- Gosset M, Berenbaum F, Thirion S, Jacques C. Primary culture and phenotyping of murine chondrocytes. Nat. Protoc. 2008;3:1253–1260. doi: 10.1038/nprot.2008.95.
- Giustarini D, Rossi R, Milzani A, Dalle-Donne I. Nitrite and nitrate measurement by Griess reagent in human plasma: Evaluation of interferences and standardization. Methods Enzymol. 2008;440:361–380. doi: 10.1016/S0076-6879(07)00823-3.
- Ogbonna AC, Clark AK, Malcangio M. Development of monosodium acetate-induced osteoarthritis and inflammatory pain in ageing mice. Age (Dordr.) 2015;37:9792. doi: 10.1007/s11357-015-9792-y.
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