Session Type: Abstract Submissions (ACR)
Background/Purpose: Osteoarthritis, the most common type of arthritis in the United States, results from trauma and other mechanical factors as well as metabolic changes in bone and cartilage. We have previously demonstrated that adenosine, acting via the A2A receptor, inhibits inflammation and plays a critical role in regulating bone metabolism. Thus, adenosine A2A receptor knockout mice are osteopenic as a result of increased osteoclast number and activity. We have observed that aging adenosine A2A receptor knockout mice experience difficulty in movement, taking food and walking and so we determined whether changes in their bone or joint structure or function could explain these changes.
Methods: 4 month old C57Bl/6 wild type (WT) and A2AKO mice (n=4) were sacrificed and knee joints were prepared for microCT analysis and histology. PAS (Periodic Acid Staining) and Trichrome staining of decalcified sections of leg were carried out. MicroCT analysis of knees of WT and KO mice were carried out and analysis of bone was performed on the distal femur below the growth plate.
Results: microCT analysis of the knees of A2AKO mice showed osteophyte formation together with mild remodeling and subchondral sclerosis when compared to WT mice. As we have previously reported A2A KO mice suffered from osteopenia; bone volume/total volume (BV/TV) was significantly decreased in A2AKO mice when compared to control (33.324±0.56 vs 35.782±0.78, respectively, p<0.01). The same decrease was observed for trabecular thickness (0.0685±0.0035 vs 0.081±0.002, p<0.05) and bone mineral density (BMD) (0.3795±0.003 vs 0.4265±0.01, respectively, p<0.5), with no change in trabecular number (4.8795±0.17 vs 4.646±0.23, p=ns). H&E and trichrome staining showed a loss in collagen in the cartilage together with diminished subchondral bone and chondrocyte hypertrophy and proliferation. PAS staining correlated with these results showing a loss in proteoglycans both in the articular cartilage and in the growth plate in A2AKO mice together with an increase in chondrocyte proliferation.
Conclusion: Deficiency in adenosine A2A receptors leads to spontaneous osteoarthritis and suggests that adenosine receptors may be novel targets for development of therapies to ameliorate or prevent osteoarthitis.
Filed a patent on use of adenosine A2AR agonists to prevent prosthesis loosening (pending). ,
B. N. Cronstein,
NIH, Gilead, Takeda, AstraZeneca,
NYU School of Medicine,
Merck-SeronoBristol-Myers Squibb, Novartis, CanFite Biopharmaceuticals, Cypress Laboratories, Regeneron (Westat, DSMB), Endocyte, Protalex, Allos, Inc., Savient, Gismo Therapeutics, Antares Pharmaceutical, Medivector,
Multiple patents on adenosine receptors and bone metabolism, pharmacology,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/adenosine-a2a-receptor-as-a-potential-new-therapeutic-target-for-the-preventiontreatment-of-osteoarthritis/