Background/Purpose Osteoarthritis results from trauma, mechanical factors or metabolic changes in bone and cartilage. Adenosine, acting via the A_2AR, inhibits inflammation and plays a critical role in regulating bone metabolism. Aging A_2AKO mice experience difficulty in movement, taking food and walking. We determined whether changes in their bone or joint structure or function could explain these changes.

Methods 8, 12 and 16 weeks old C57Bl/6 wild type (WT) and A_2AKO mice (n=5) were sacrificed and knee joints were prepared for microCT and histology. PAS (Periodic Acid Staining), Safranin-O and Trichrome staining were carried out. MicroCT analysis of knees was performed on the distal femur below the growth plate. Immunostaining for MMP-13 and Collagen-X were performed. Human immortalized chondrocytes (TC28a2) and primary osteoarthritic chondrocytes were treated with A_2AR agonist CGS21680 1μM in the presence/absence of the A_2AR antagonist ZM241385 1μM. Collagen-X, MMP-13 and b-catenin were analyzed by Western Blot and ELISA.

Results microCT analysis of A_2AKO mice knees showed osteophyte formation together with mild remodeling and subchondral sclerosis when compared to WT starting at 8 weeks of age. Bone volume/total volume was significantly decreased in A_2AKO mice when compared to WT (33.324±0.56 vs 35.782±0.78, respectively, p<0.01). Trabecular thickness was also decreased (0.0685±0.0035 vs 0.081±0.002, p<0.05) together with bone mineral density (0.3795±0.003 vs 0.4265±0.01 respectively, p<0.5). Trichrome, Safranin-O and PAS staining of A_2AKO articular cartilage showed chondrocyte hyperthrophy with a reduction of collagen and proteoglycans. Immunostaining for MMP-13 and Collagen-X showed an increase in these biomarkers in A_2AKO mice. In both TC28a2 and primary human chondrocytes, activation of A_2AR by CGS21680 induced a significant decrease in Collagen-X and MMP-13 expression and release, with an increase in b-catenin expression. These effects are reversed by the A_2AR antagonist ZM241385.

Conclusion Deficiency in adenosine A_2AR leads to spontaneous osteoarthritis and stimulation of A_2ARs on chondrocytes diminishes changes associated with osteoarthritis, findings that  suggest that A_2AR may be novel targets for development of therapies to ameliorate or prevent osteoarthitis.

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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-2/