Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose Prior studies demonstrate that adenosine, acting at A2AR, mediates the anti-inflammatory effects of methotrexate (MTX) in models of both acute and chronic inflammation. We have previously reported that adenosine A2AR ligation diminishes wear particle-driven osteolysis. We asked whether MTX treatment could prevent bone resoprtion due to inflammatory osteolysis.
Methods
MTX (1mg/kg) was administered intraperitoneally to C57B/6 mice on a weekly basis starting 2 weeks prior to surgery. Control mice were injected with 0.9% saline. 1cm midline sagittal incisions were made over calvaria in 6-8 wk old C57Bl/6 mice. Calvaria were exposed to 20µl of PBS containing 3mg of UHMWPE followed by daily injections of either vehicle (Control and MTX) or ZM241385 1µM (A2AR antagonist) (n=5 each) for 14 days. XenoLight Rediject Bone Probe was injected IV and fluorescence of calvaria measured (IVIS) to assay bone formation. MicroCT and immunostaining for osteoclast and osteoblast markers were performed.
Results XenoLight imaging revealed an 80±10% increase in bone formation after exposure to MTX when compared to UHMWPE alone (p<0.001, n=5) and ZM241385 completely reversed this effect (11±5% increase vs. control, p=NS, n=5). microCT analysis revealed increased porosity in particle-exposed mice that was inhibited by MTX treatment (54±6% decreased compared to saline treatment, p<0.001, n=5) an effect abrogated by ZM241385. MTX significantly increased bone volume/total volume (BV/TV) (9.54±0.1 vs 8.68±0.2, p<0.05), BV (5.31±0.3 vs 4.15±0.2, p<0.05), TV (5.90±0.2 vs 3.76±0.2, p<0.001) and Bone Mineral Density (BMD) (153.75±0.4 vs 144.63±1, p<0.001) when compared to WT, and ZM241385 completely reversed this effect. Histological examination of particle-exposed mouse calvarias demonstrated an inflammatory infiltrate on the bone surface that was significantly reduced by MTX and treatment with ZM241385 completely reversed this effect.
Conclusion These results indicate that treatment with MTX, a well-tolerated and commonly used anti-inflammatory drug, may provide a novel therapeutic approach to enhance orthopedic implant survival, delaying or eliminating the need for revision arthroplasty surgery.
Disclosure:
A. Mediero,
None;
T. Wilder,
None;
B. N. Cronstein,
Canfite Pharma,
1,
AstraZeneca,
2,
Cellgene,
2,
Gilead,
2,
NIH,
2,
NYU School of Medicine,
3,
Bristol-Myers Squibb,
5,
Pfizer Inc,
5,
Eli Lilly and Company,
5,
Rheumatology Reseach Foundation,
6,
ACR,
6,
Arthritis Foundation,
6.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/methotrexate-prevents-inflammatory-osteolysis-by-activation-of-the-adenosine-a2a-receptor-a2ar/