Date: Monday, November 9, 2015
Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: Adenosine, acting at its receptors, regulates chondrocyte function and inflammation, two components of OA. Mice lacking adenosine A2A receptors (A2AR) have increasing difficulty walking as they age. We report here that A2ARKO mice have changes consistent with OA in their knees and treatment with a liposomal adenosine (lipado) suspension abrogates development of OA in a rat anterior cruciate ligament (ACL) injury model of OA.
Methods: Knee joints of WT and A2ARKO mice (n=5/group) were studied by micro-computed (µCT) analysis and immunohistochemistry. Locomotor activity in mice was measured with open-field and rotarod tests. Primary articular chondrocytes from neonatal WT or A2ARKO mice were studied for altered expression of OA markers. OA was induced in rats by mechanical rupture of ACL. Rats (n=3/group) were treated with intra-articular injection of 100µl of saline, a liposomal formulation containing adenosine (10 mg/Kg) or empty liposomes (lipo) and weight and knee swelling of the rats were monitored. Rat legs were harvested after 56 days to evaluate the joints and plasma cytokine levels were quantitated in rats, WT and A2ARKO mice.
Results: A2ARKO mice did not move as far as WT mice (A2ARKO=664±123 cm vs WT=1404±128 cm, p<0.001); nor did they move as fast (A2ARKO=1.11±0.21 cm/sec vs WT=2.34±0.21 cm/sec, p<0.001) and fell more quickly from the rotarod apparatus (A2ARKO=86±11sec vs WT=145±22 sec, p<0.05). A2ARKO mice had progressive joint damage consistent with OA (e.g. OARSI score at 16 weeks for A2ARKO=3.7±0.6 vs WT=1.5±0.2, p<0.01). In contrast, knee joints of 19wk old A2BRKO mice did not differ from WT. Chondrocytes isolated from neonatal A2ARKO mice, but not WT, spontaneously expressed and secreted collagen X, fibronectin, osteopontin and MMP-13. Rats treated with intra-articular lipado were significantly less swollen (difference between uninjured and injured knee was 2.32±0.07mm for saline group, 2.35±0.36mm for lipo-treated and 0.93±0.12mm for lipado-treated, p<0.01, 1-way ANOVA). Macroscopic evaluation of joints showed near-normal appearing cartilage in lipado-treated rats but pitting and loss of cartilage in saline or lipo-treated rats. There was a marked reduction of subchondral bone changes in µCTs of lipado-treated mice as well and plasma levels of IL-1b, IL-6, IFNg, IL-5, TNFa and RANTES were significantly lower in rats treated with lipado.
Conclusion: These findings suggest that the presence and tonic activation of A2AR in the joint are important for maintaining joint homeostasis. Moreover these results suggest that adenosine receptors may be a novel target for treatment of OA.
To cite this abstract in AMA style:CORCIULO C, Lendhey M, RAMME A, Wilder T, KENNEDY O, Cronstein B. Adenosine A2A Receptor, but Not A2B Receptor, Deletion Leads to Development of Osteoarthritis (OA) in Mice and Administration of a Liposomal Suspension of Adenosine Prevents/Treats Osteoarthritis in Rats [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/adenosine-a2a-receptor-but-not-a2b-receptor-deletion-leads-to-development-of-osteoarthritis-oa-in-mice-and-administration-of-a-liposomal-suspension-of-adenosine-preventstreats-osteoarthritis-in-r/. Accessed January 29, 2020.
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