Abstract
Background
Osteoarthritis (OA) is a chronic disease that may lead to joint structure degeneration, cartilage destruction, osteophyte formation, subchondral bone disruption, and pain. In this scenario, a higher proportion of the proinflammatory macrophage type 1 (M1) than the anti-inflammatory macrophage type 2 (M2) could be highlighted as a hallmark of OA progression. The balance between these two macrophage types emerges as a new therapeutic target in OA. This study aimed to evaluate the analgesia and macrophage profile in the treatment of experimental osteoarthritis (EOA) with systemic dimethyl fumarate (DMF) or local intra-articular monomethyl fumarate (MMF).
Results
DMF via gavage or MMF via intra-articular in the right knee of EOA rats showed improvements in gait parameters and the nociceptive recovery of the mechanical threshold assessment by adapted electronic von Frey treatment on the twenty-first day (long-lasting phase). DMF treatment decreased proinflammatory TNF-α while increasing anti-inflammatory IL-10 cytokines from the macerated capsule on the fifth day (inflammatory phase). MMF treatment showed joint capsule mRNA extraction downregulating iNOS and TNF-α gene expression while upregulating IL-10 and MCP-1. However, CD206 was not significant but higher than untreated EOA rats’ joints on the seventh day (inflammatory phase).
Conclusions
Our studies with EOA model induced by MIA suggest a new perspective for human treatment committed with OA based on macrophage polarization as a therapeutic target, switching the proinflammatory profile M1 to the anti-inflammatory profile M2 with DMF systematic or by MMF locally treatment according to the OA severity.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The datasets generated during the current study are available from the corresponding author upon reasonable request.
Abbreviations
- OA:
-
Osteoarthritis
- EOA:
-
Experimental osteoarthritis
- MS:
-
Multiple sclerosis
- CNS:
-
Central nervous system
- PNS:
-
Peripheral nervous system
- M1:
-
Macrophage type 1
- M2:
-
Macrophage type 2
- IL:
-
Interleukin
- Arg-1:
-
Arginase-1
- iNOS:
-
Inducible nitric oxide synthase
- NO:
-
Nitric oxide
- TGF-β:
-
Transforming growth factor
- DMF:
-
Dimethyl fumarate
- MMF:
-
Monomethyl fumarate
- Nrf2:
-
Nuclear transcription factor derived from erythroid type 2
- bZIP:
-
Basic leucine zipper protein
- Keap1:
-
Kelch-like ECH-associated protein
- MMP:
-
Matrix metalloproteinases
- NSAIDs:
-
Non-steroidal anti-inflammatory drugs
- PGE2:
-
Prostaglandin-E2
- DAMPs:
-
Damage associated with molecular pattern
- PAMPs:
-
Pathogens associated with molecular patterns
- LPS:
-
Lipopolysaccharide
- INF-γ:
-
Interferon-gamma
- TNF-α:
-
Tumor necrosis factor alpha
- Nf-κß:
-
Nuclear factor-kappa B
- ROS:
-
Reactive oxygen species
References
Akkiraju H, Nohe A (2015) Role of chondrocytes in cartilage formation, progression of osteoarthritis and cartilage regeneration. J Dev Biol 3:177–192. https://doi.org/10.3390/jdb3040177
Anandacoomarasamy A, March L (2010) Current evidence for osteoarthritis treatments. Ther Adv Musculoskelet Dis 2:17–28. https://doi.org/10.1177/1759720X09359889
Ayhan E, Kesmezacar H, Akgun I (2014) Intraarticular injections (corticosteroid, hyaluronic acid, platelet rich plasma) for the knee osteoarthritis. World J Orthop 5:351–361. https://doi.org/10.5312/wjo.v5.i3.351
Carlström KE, Ewing E, Granqvist M et al (2019) Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes. Nat Commun. https://doi.org/10.1038/s41467-019-11139-3
Chen Y, Jiang W, Yong H et al (2020) Macrophages in osteoarthritis: pathophysiology and therapeutics. Am J Transl Res 12:261–268
Coimbra IB, Plapler PG, de Campos GC (2019) Generating evidence and understanding the treatment of osteoarthritis in Brazil: a study through delphi methodology. Clinics 74:1–7. https://doi.org/10.6061/clinics/2019/e722
Conaghan PG, Cook AD, Hamilton JA, Tak PP (2019) Therapeutic options for targeting inflammatory osteoarthritis pain. Nat Rev Rheumatol 15:355–363. https://doi.org/10.1038/s41584-019-0221-y
Cui A, Li H, Wang D et al (2020) Global, regional prevalence, incidence and risk factors of knee osteoarthritis in population-based studies. EClinicalMedicine 29–30:100587. https://doi.org/10.1016/j.eclinm.2020.100587
Da Costa BR, Pereira TV, Saadat P et al (2021) Effectiveness and safety of non-steroidal anti-inflammatory drugs and opioid treatment for knee and hip osteoarthritis: Network meta-analysis. BMJ. https://doi.org/10.1136/bmj.n2321
De Sousa VJ (2019) The pharmacology of pain associated with the monoiodoacetate model of osteoarthritis. Front Pharmacol 10:1–8. https://doi.org/10.3389/fphar.2019.00974
De Abreu CL, Ottoni MHF, Dos Santos MG et al (2017) Dimethyl sulfoxide (DMSO) decreases cell proliferation and TNF-α, IFN-, and IL-2 cytokines production in cultures of peripheral blood lymphocytes. Molecules 22:1–10. https://doi.org/10.3390/molecules22111789
Felson DT, Neogi T (2018) Emerging treatment models in rheumatology: challenges for osteoarthritis trials. Arthritis Rheumatol 70:1175–1181. https://doi.org/10.1002/art.40515
Fernandes TL, Gomoll AH, Lattermann C et al (2020) Macrophage: a potential target on cartilage regeneration. Front Immunol 11:1–9. https://doi.org/10.3389/fimmu.2020.00111
Ferreira-Gomes J, Adães S, Castro-Lopes JM (2008) Assessment of movement-evoked pain in osteoarthritis by the knee-bend and catwalk tests: a clinically relevant study. J Pain 9:945–954. https://doi.org/10.1016/j.jpain.2008.05.012
Gao SJ, Li DY, Liu DQ et al (2022) Dimethyl fumarate attenuates pain behaviors in osteoarthritis rats via induction of Nrf2-mediated mitochondrial biogenesis. Mol Pain 18:1–12. https://doi.org/10.1177/17448069221124920
Garrick JM, Costa LG, Cole TB, Marsillach J (2021) Evaluating gait and locomotion in rodents with the CatWalk. Curr Protoc 1:1–22. https://doi.org/10.1002/cpz1.220
Gillard GO, Collette B, Anderson J et al (2015) DMF, but not other fumarates, inhibits NF-κB activity in vitro in an Nrf2-independent manner. J Neuroimmunol 283:74–85. https://doi.org/10.1016/j.jneuroim.2015.04.006
Grässel S, Muschter D (2020) Recent advances in the treatment of osteoarthritis. F1000Res 9:1 (17 Version 1 ; Peer Review : 3 Approved)
Guerrero ATG, Verri WA, Cunha TM et al (2006) Hypernociception elicited by tibio-tarsal joint flexion in mice: a novel experimental arthritis model for pharmacological screening. Pharmacol Biochem Behav 84:244–251. https://doi.org/10.1016/j.pbb.2006.05.008
Jones IA, Togashi R, Wilson ML et al (2019) Intra-articular treatment options for knee osteoarthritis. Nat Rev Rheumatol 15(2):77–90
Kara H, Çağlar C, Asiltürk M et al (2021) Comparison of a manual walking platform and the CatWalk gait analysis system in a rat osteoarthritis model. Adv Clin Exp Med 30:949–956. https://doi.org/10.17219/ACEM/137536
Kennedy A, Fearon U, Veale DJ, Godson C (2011) Macrophages in synovial inflammation. Front Immunol 2:1–9. https://doi.org/10.3389/fimmu.2011.00052
Kobayashi EH, Suzuki T, Funayama R et al (2016) Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun 7:1–14. https://doi.org/10.1038/ncomms11624
Koda K, Hyakkoku K, Ogawa K et al (2016) Sensitization of TRPV1 by protein kinase C in rats with mono-iodoacetate-induced joint pain. Osteoarthr Cartil 24:1254–1262. https://doi.org/10.1016/j.joca.2016.02.010
Kourakis S, Timpani CA, de Haan JB et al (2020) Dimethyl fumarate and its esters: a drug with broad clinical utility? Pharmaceuticals 13:1–15. https://doi.org/10.3390/ph13100306
Kuner R (2010) Central mechanisms of pathological pain. Nat Med 16:1258–1266. https://doi.org/10.1038/nm.2231
Lakes EH, Allen KD (2016) Gait analysis methods for rodent models of arthritic disorders: reviews and recommendations. Osteoarthr Cartil 24:1837–1849. https://doi.org/10.1016/j.joca.2016.03.008
Lategan TW, Wang L, Sprague TN, Rousseau FS (2021) Pharmacokinetics and bioavailability of monomethyl fumarate following a single oral dose of bafiertam™ (Monomethyl Fumarate) or Tecfidera® (Dimethyl Fumarate). CNS Drugs 35:567–574. https://doi.org/10.1007/s40263-021-00799-9
Lin YS, Huang MH, Chai CY et al (2018) Randomized controlled trial on low level laser therapy (LLLT) in the treatment of osteoarthritis (OA) of the hand. Lasers Med Sci 32:e90. https://doi.org/10.1016/j.joca.2009.03.002.Aging
Lv M, Zhou Y, Polson SW et al (2019) Identification of chondrocyte genes and signaling pathways in response to acute joint inflammation. Sci Rep 9:1–12. https://doi.org/10.1038/s41598-018-36500-2
Ma Y, Yang H, Zong X et al (2021) Artificial M2 macrophages for disease-modifying osteoarthritis therapeutics. Biomaterials 274:120865. https://doi.org/10.1016/j.biomaterials.2021.120865
Mora JC, Przkora R, Cruz-Almeida Y (2018) Knee osteoarthritis: pathophysiology and current treatment modalities. J Pain Res 11:2189–2196. https://doi.org/10.2147/JPR.S154002
Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11:723–737. https://doi.org/10.1038/nri3073
Mushenkova NV, Nikiforov NG, Shakhpazyan NK et al (2022) Phenotype diversity of macrophages in osteoarthritis: implications for development of macrophage modulating therapies. Int J Mol Sci 23:8381. https://doi.org/10.3390/ijms23158381
Ni F, Zhang Y, Peng X, Li J (2020) Correlation between osteoarthritis and monocyte chemotactic protein-1 expression: a meta-analysis. J Orthop Surg Res 15:1–9. https://doi.org/10.1186/s13018-020-02045-2
Pålsson-McDermott EM, O’Neill LAJ (2020) Targeting immunometabolism as an anti-inflammatory strategy. Cell Res 30:300–314. https://doi.org/10.1038/s41422-020-0291-z
Pitarokoili K, Ambrosius B, Meyer D et al (2015) Dimethyl fumarate ameliorates lewis rat experimental autoimmune neuritis and mediates axonal protection. PLoS ONE 10:1–17. https://doi.org/10.1371/journal.pone.0143416
Rim YA, Ju JH (2021) The role of fibrosis in osteoarthritis progression. Life 11:1–13. https://doi.org/10.3390/life11010003
Saha S, Saha L, Singh N et al (2020) To study the effect and mechanism of dimethyl fumarate [DMF ] in adjuvant induced arthritis model in rats. Rheum Res. https://doi.org/10.22631/rr.2020.69997.1101
Shapouri-Moghaddam A, Mohammadian S, Vazini H, et al (2018) Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol 233:6425–6440
Singh N, Vijayanti S, Saha L et al (2018) Neuroprotective effect of Nrf2 activator dimethyl fumarate, on the hippocampal neurons in chemical kindling model in rat. Epilepsy Res 143:98–104. https://doi.org/10.1016/j.eplepsyres.2018.02.011
Tardito S, Martinelli G, Soldano S et al (2019) Macrophage M1/M2 polarization and rheumatoid arthritis: a systematic review. Autoimmun Rev 18:102397. https://doi.org/10.1016/j.autrev.2019.102397
Tateiwa D, Yoshikawa H, Kaito T (2019) Cartilage and bone destruction in arthritis: pathogenesis and treatment strategy: a literature review. Cells. https://doi.org/10.3390/cells8080818
Teixeira JM, Bobinski F, Parada CA et al (2017) P2X3 and P2X2/3 receptors play a crucial role in articular hyperalgesia development through inflammatory mechanisms in the knee joint experimental synovitis. Mol Neurobiol 54:6174–6186. https://doi.org/10.1007/s12035-016-0146-2
Thimmulappa RK, Lee H, Rangasamy T et al (2006) Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest 116:984–995. https://doi.org/10.1172/JCI25790
Thomson A, Hilkens CMU (2021) Synovial macrophages in osteoarthritis: the key to understanding pathogenesis? Front Immunol 12:1–9. https://doi.org/10.3389/fimmu.2021.678757
Thysen S, Luyten FP, Lories RJU (2015) Targets, models and challenges in osteoarthritis research. DMM Dis Model Mech 8:17–30. https://doi.org/10.1242/dmm.016881
Udo M, Muneta T, Tsuji K et al (2016) Monoiodoacetic acid induces arthritis and synovitis in rats in a dose- and time-dependent manner: proposed model-specific scoring systems. Osteoarthr Cartil 24:1284–1291. https://doi.org/10.1016/j.joca.2016.02.005
Vieira WF, Malange KF, de Magalhães SF et al (2020) Gait analysis correlates mechanical hyperalgesia in a model of streptozotocin-induced diabetic neuropathy: a CatWalk dynamic motor function study. Neurosci Lett 736:135253. https://doi.org/10.1016/j.neulet.2020.135253
Wang L, He C (2022) Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis. Front Immunol 13:1–20. https://doi.org/10.3389/fimmu.2022.967193
Warmink K, Vinod P, Korthagen NM et al (2023) Macrophage-driven inflammation in metabolic osteoarthritis: implications for biomarker and therapy development. Int J Mol Sci. https://doi.org/10.3390/ijms24076112
Wu CL, Harasymowicz NS, Klimak MA et al (2020) The role of macrophages in osteoarthritis and cartilage repair. Osteoarthr Cartil 28:544–554. https://doi.org/10.1016/j.joca.2019.12.007
Xu J, Yan L, Yan B et al (2020) Osteoarthritis pain model induced by intra-articular injection of mono-iodoacetate in rats. J vis Exp 2020:1–7. https://doi.org/10.3791/60649
Yusuf E (2016) Pharmacologic and Non-Pharmacologic Treatment of Osteoarthritis. Curr Treat Options Rheumatol 2:111–125. https://doi.org/10.1007/s40674-016-0042-y
Zhang H, Cai D, Bai X (2020) Macrophages regulate the progression of osteoarthritis. Osteoarthr Cartil 28:555–561. https://doi.org/10.1016/j.joca.2020.01.007
Acknowledgements
The present project 88882.461722/2019-01 was supported by the Higher Education Personnel Improvement Coordination—CAPES. The authors gratefully acknowledge the support of the Laboratory of Nerve Regeneration at the Institute of Biology (IB/Unicamp) and the Department of Translational Medicine (FCM/Unicamp).
Funding
The present project 88882.461722/2019-01 was supported by the Higher Education Personnel Improvement Coordination—CAPES, Brazil. Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, 88882.461722/2019-01, Douglas Menezes de Souza
Author information
Authors and Affiliations
Contributions
Douglas Menezes de Souza: conceptualization, methodology, validation, formal analysis, investigation, writing—original draft, writing—review and editing, visualization, and funding acquisition; Catarine Massucato Nishijima contributed by supporting in vitro and behavioral analyses, drugs dilution, and manuscript preparation; Kauê Franco Malange contributed by teaching behavioral experiments, study design and manuscript preparation; Bruno Henrique de Melo Lima contributed teaching and performing behavioral experiments in catwalk, and manuscript preparation; Vinícius Capetini performed RT-PCR experiments and supported in manuscript preparation; Alexandre Leite Rodrigues de Oliveira contributed to the methodology and resources for the catwalk procedure; Gabriel Forato Anhê contributed to the methodology and resources for RT-PCR; Claudia Herrera Tambeli contributed writing, reviewing, and editing the manuscript; Carlos Amilcar Parada contributed in the conceptualization, resources, writing—original draft, writing—review and editing manuscript, supervision, project administration, and funding acquisition.
Corresponding authors
Ethics declarations
Conflict of interests
The authors declare that they have no competing interests.
Ethical approval and consent to participate
The experiment was approved by the Ethics Committee on the Use of Animals (CEUA for protocol 5965-1/2021 on March 21st, 2022. All experiments were conducted and performed according to the guidelines of the National Council for Animal Experimentation Control (CONCEA).
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
de Souza, D.M., Malange, K.F., Nishijima, C.M. et al. Intraarticular monomethyl fumarate as a perspective therapy for osteoarthritis by macrophage polarization. Inflammopharmacol 32, 1239–1252 (2024). https://doi.org/10.1007/s10787-024-01443-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10787-024-01443-w