IB-MECA, an A3 adenosine receptor agonist prevents bone resorption in rats with adjuvant induced arthritis.
OBJECTIVE
The anti-inflammatory effect of adenosine is partially mediated via the A3 adenosine receptor (A3AR), a Gi protein associated cell surface receptor. The highly selective A3AR agonist, IB-MECA was earlier shown to prevent the clinical and pathological manifestations of arthritis in experimental animal models of collagen and adjuvant induced arthritis (AIA). In this study we tested the effect of IB-MECA on the prevention of bone resorption in AIA rats and looked at the molecular mechanism of action.


METHODS
Rats with AIA were treated orally twice daily with IB-MECA starting upon onset of disease and the clinical score was evaluated every other day. At study termination the foot, knee and hip region of both vehicle and IB-MECA treated animals were subjected to histomorphometric analysis. Western blot analysis was carried out on paw protein extracts.


RESULTS
IB-MECA ameliorated the clinical manifestations of the disease and reduced pannus and fibrosis formation, attenuated cartilage and bone destruction and decreased the number of osteoclasts. In cell protein extracts derived from paw of AIA rats, A3AR was highly expressed in comparison to naïve animals. In paw extracts derived from IB-MECA treated AIA rats, down-regulation of the A3AR protein expression level was noted. PI3K, PKB/Akt, IKK, NF-kappaB, TNF-alpha and RANKL were down-regulated whereas caspase 3 was up-regulated.


CONCLUSIONS
IB-MECA, a small highly bioavailable molecule, induces modulation of proteins which control survival and apoptosis resulting in the amelioration of the inflammatory process and the preservation of bone mass in AIA rats.
Rath-Wolfson
L
L
Can-Fite BioPharma Ltd., Kiryat-Matalon, Petah-Tikva, Israel.
Bar-Yehuda
S
S
Madi
L
L
Ochaion
A
A
Cohen
S
S
Zabutti
A
A
Fishman
P
P
D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058909:Adenosine A3 Receptor Agonists; D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001862:Bone Resorption / Q000517:prevention & control*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology; D006614:Hindlimb / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007596:Joints / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D043684:Receptor, Adenosine A3 / Q000378:metabolism
D058909:Adenosine A3 Receptor Agonists; D050071:Bone Density Conservation Agents; D043684:Receptor, Adenosine A3; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D000241:Adenosine