Abstract
Rheumatoid arthritis (RA) is immune-mediated, inflammatory disease that affects synovial joints, and characterized by inflammatory changes in synovial tissue, cartilage, bone, and less commonly in extra-articular structures. Docetaxel (DTX) is a semi-synthetic anti-neoplastic medication. Peptidyl-arginine deiminase type 4 (PAD4) is expressed in macrophages and neutrophils in RA synovial membrane. Their effectiveness is in producing anti-cyclic citrullinated peptide antibodies (ACPA)-targeted citrullinated neoepitopes.
Aim
To evaluate the anti-inflammatory effects of DTX in RA and the effect of methotrexate on PAD4 to investigate its potential as an RA biomarker.
Methods
Forty male Wistar rats were divided into five groups of eight rats. Healthy rats formed the control group. The Second Group to Fifth group were induced with Complete Freund’s adjuvant. The third group received DTX at a dosage of 1 mg/kg on alternate days, as determined by a preliminary experiment. The fourth group was given 1 mg/kg/week of methotrexate intraperitoneally. The fifth group was treated with a half dose of DTX and methotrexate simultaneously.
Results
Significant Arthritis index and knee joint circumference decrease in the DTX group. No significant difference in body weight, platelet–lymphocyte ratio, and white blood cell count between the groups. Neutrophile lymphocyte ratio showed weak correlation with ACPA, while PAD4 showed good correlation with RA markers. Level of ACPA, PAD4, TNF-α, IL-1β, and VEGF significantly decreased in the DTX group than induction group (p < 0.05).
Conclusion
DTX reduces the progression and joint destruction in rats induced by Complete Freund’s Adjuvant which may due to inhibition of PAD4, TNF-α, IL-1β, VEGF, and ACPA. Also, methotrexate exhibited anti PAD4 effect.
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The data used and analyzed during the current study are available from the corresponding author upon reasonable request.
Abbreviations
- ACPA:
-
Anti-cyclic citrullinated peptide antibodies
- AI:
-
Arthritis index
- AIA:
-
Adjuvant induced arthritis
- ANOVA:
-
Analysis of variance
- CFA:
-
Complete Freund’s adjuvant
- DMARD:
-
Disease modifying antirheumatic drugs
- DTX:
-
Docetaxel
- ELISA:
-
Enzyme linked immunosorbent assay
- FLS:
-
Fibroblast like synovitis
- i.p:
-
Intraperitoneal
- IHC:
-
Immunohistochemistry
- IL-1β:
-
Interleukin- 1beta
- KJC:
-
Knee joint circumference
- MAPK:
-
Mitogen activated protein kinase
- MMP:
-
Matrix metalloprotease
- MTX:
-
Methotrexate
- NET:
-
Neutrophile extracellular trap
- NF-kB:
-
Nuclear factor kappa B
- Ng:
-
Nanogram
- Pg:
-
Picogram
- PAD4:
-
Peptidyl-arginine deiminase type 4
- Q.O.D:
-
Every other day—on alternative day
- RA:
-
Rheumatoid arthritis
- RF:
-
Rheumatoid factor
- STDEV:
-
Standard deviation
- TNF-α:
-
Tumor necrosis factor-alpha
- VEGF:
-
Vascular endothelial growth factor
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The authors thank the College of Pharmacy/Mustansiriyah University https://www.uomustansiriyah.edu.iq for approving and supporting this study which is part of the dissertation of a master’s student.
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O.M.A., G.A.J. and S.Y.J. contributed to the design of the research. O.M.A. performed the experiments. O.M.A. and G.A.J. analyzed the data. O.M.A. collected the samples. O.M.A wrote the manuscript. G.A.J. and S.Y.J. supervised all the work and reviewed the manuscript. All authors read and approved the final manuscript.
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Alghulami, O.M., Jasim, G.A. & Jasim, S.Y. Evaluating the docetaxel effect in an animal model of polyarthritis. Inflammopharmacol (2024). https://doi.org/10.1007/s10787-024-01459-2
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DOI: https://doi.org/10.1007/s10787-024-01459-2