Background & Aims
One of the most common bone diseases, osteoarthritis (OA) affects 7% of the global population. OA is a chronic disease, characterized by lower inflammation resulting in subchondral and cartilage disruption, osteophyte formation, and pain. According to the OA progression, macrophage cells have been associated with this period. They are essential and versatile cells responsible for eliminating pathogens and healing tissue. A Higher pro-inflammatory macrophage type 1 (M1) than anti-inflammatory macrophage type 2 (M2) is highlighted as a hallmark in OA, triggering pain signals. In this way, the balance between these two macrophage profiles emerges as a new therapeutic target in OA. Our study has aimed to evaluate the analgesia and macrophage profile in the treatment of experimental osteoarthritis (EOA) with a single dose by an intraarticular pathway with monomethyl Fumarate (MMF).
Methods
The ethics committee has approved (CEUA number 5965-1/2021). The current study induced EOA in rats (Wistar males) with mono-iodine acetate (MIA). Three days post-MIA injection, EOA animals received a single treatment by intra-articular injection with a single dose of 280 ng of MMF in the right knee. During this period, behavioral analyses were performed for 21 days, verified by Catwalk or adapted electronic von Frey on days 0 (basal), and three days post-MIA injection 1, 3, 5, 7, 14, and 21. On the 5th day (inflammatory phase) and 21st day (chronic phase), the right knee capsule joint was collected to analyze the gene and marker related to the macrophage profile by RT-PCR. Bone marrow-derived macrophages were plated and polarized to the M1 profile (LPS + IFN-?) and incubated with 50 µM of MMF. At the end of this experiment, cells were lysed, and the genes iNOS (M1) and ARG-1 (M2) were analyzed by RT-PCR. Statistical analyses were performed with one-way or two-way ANOVA (P <0.05).
Results
A previous study using daily dimethyl fumarate (DMF) in EOA rats via gavage indicates a decrease in pro-inflammatory cytokines while increasing anti-inflammatory cytokines during the inflammatory period (7th days post-MIA injection). This treatment suggests reducing hyperalgesia in EOA rats by analyses of adapted electronic von Frey and gait parameters (Catwalk), demonstrating to diminish pain sensitization (21st days post-MIA injection). The treatment with MMF (single dose) via intra-articular in the right knee of EOA rats showed improvements in gait parameters (Catwalk) and earlier nociceptive recovery of the mechanical threshold assessment by adapted electronic von Frey for 21st days (long-lasting phase). Observing the inflammatory phase (5th day), MMF treatment in EOA rats suggests downregulating iNOS and TNF-? gene expression while upregulating IL-10 and MCP-1 in the macerate joint capsule (right knee). Further studies are being investigated to understand macrophage roles in OA.
Conclusions
Our studies with the 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 pro-inflammatory profile M1 to the anti-inflammatory profile M2 with MMF local treatment. However, more studies are fully required to understand the MMF treatment and the role of macrophage (M2) to promote cartilage repair and reduce pain signals.
References
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
Grässel S, Muschter D (2020) Recent advances in the treatment of osteoarthritis [ version 1?; peer review?: 3 approved ]. F1000Research 9:1–17
Han R, Xiao J, Zhai H, Hao J (2016) Dimethyl fumarate attenuates experimental autoimmune neuritis through the nuclear factor erythroid-derived 2-related factor 2/hemoxygenase-1 pathway by altering the balance of M1/M2 macrophages. J Neuroinflammation 13:1–14. https://doi.org/10.1186/s12974-016-0559-x
Raoof R, Gil CM, Lafeber FPJG, et al (2021) Dorsal root ganglia macrophages maintain osteoarthritis pain. J Neurosci 41:8249–8261. https://doi.org/10.1523/JNEUROSCI.1787-20.2021
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Presenting Author
Douglas Menezes de Souza
Poster Authors
Topics
- Models: Acute Pain