TY - JOUR
T1 - Induction of an antiinflammatory effect and prevention of cartilage damage in rat knee osteoarthritis by CF101 treatment
AU - Bar-Yehuda, S.
AU - Rath-Wolfson, L.
AU - Del Valle, L.
AU - Ochaion, A.
AU - Cohen, S.
AU - Patoka, R.
AU - Zozulya, G.
AU - Barer, F.
AU - Atar, E.
AU - Piña-Oviedo, S.
AU - Perez-Liz, G.
AU - Castel, D.
AU - Fishman, P.
PY - 2009
Y1 - 2009
N2 - Objective. Studies have suggested that rheumatoid arthritis (RA) and osteoarthritis (OA) share common characteristics. The highly selective A 3 adenosine receptor agonist CF101 was recently defined as a potent antiinflammatory agent for the treatment of RA. The purpose of this study was to examine the effects of CF101 on the clinical and pathologic manifestations of OA in an experimental animal model. Methods. OA was induced in rats by monosodium iodoacetate, and upon disease onset, oral treatment with CF101 (100 μg/kg given twice daily) was initiated. The A3 adenosine receptor antagonist MRS1220 (100 μg/kg given twice daily) was administered orally, 30 minutes before CF101 treatment. The OA clinical score was monitored by knee diameter measurements and by radiographic analyses. Histologic analyses were performed following staining with hematoxylin and eosin, Safranin O-fast green, or toluidine blue, and histologic changes were scored according to a modified Mankin system. Signaling proteins were assayed by Western blotting; apoptosis was detected via immunohistochemistry and TUNEL analyses. Results. CF101 induced a marked decrease in knee diameter and improved the changes noted on radiographs. Administration of MRS1220 counteracted the effects of CF101. CF101 prevented cartilage damage, osteoclast/osteophyte formation, and bone destruction. In addition, CF101 markedly reduced pannus formation and lymphocyte infiltration. Mechanistically, CF101 induced deregulation of the NF-κB signaling pathway, resulting in down-regulation of tumor necrosis factor α. Consequently, CF101 induced apoptosis of inflammatory cells that had infiltrated the knee joints; however, it prevented apoptosis of chondrocytes. Conclusion. CF101 deregulated the NF-κB signaling pathway involved in the pathogenesis of OA. CF101 induced apoptosis of inflammatory cells and acted as a cartilage protective agent, which suggests that it would be a suitable candidate drug for the treatment of OA.
AB - Objective. Studies have suggested that rheumatoid arthritis (RA) and osteoarthritis (OA) share common characteristics. The highly selective A 3 adenosine receptor agonist CF101 was recently defined as a potent antiinflammatory agent for the treatment of RA. The purpose of this study was to examine the effects of CF101 on the clinical and pathologic manifestations of OA in an experimental animal model. Methods. OA was induced in rats by monosodium iodoacetate, and upon disease onset, oral treatment with CF101 (100 μg/kg given twice daily) was initiated. The A3 adenosine receptor antagonist MRS1220 (100 μg/kg given twice daily) was administered orally, 30 minutes before CF101 treatment. The OA clinical score was monitored by knee diameter measurements and by radiographic analyses. Histologic analyses were performed following staining with hematoxylin and eosin, Safranin O-fast green, or toluidine blue, and histologic changes were scored according to a modified Mankin system. Signaling proteins were assayed by Western blotting; apoptosis was detected via immunohistochemistry and TUNEL analyses. Results. CF101 induced a marked decrease in knee diameter and improved the changes noted on radiographs. Administration of MRS1220 counteracted the effects of CF101. CF101 prevented cartilage damage, osteoclast/osteophyte formation, and bone destruction. In addition, CF101 markedly reduced pannus formation and lymphocyte infiltration. Mechanistically, CF101 induced deregulation of the NF-κB signaling pathway, resulting in down-regulation of tumor necrosis factor α. Consequently, CF101 induced apoptosis of inflammatory cells that had infiltrated the knee joints; however, it prevented apoptosis of chondrocytes. Conclusion. CF101 deregulated the NF-κB signaling pathway involved in the pathogenesis of OA. CF101 induced apoptosis of inflammatory cells and acted as a cartilage protective agent, which suggests that it would be a suitable candidate drug for the treatment of OA.
UR - http://www.scopus.com/inward/record.url?scp=70349778666&partnerID=8YFLogxK
U2 - 10.1002/art.24817
DO - 10.1002/art.24817
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C2 - 19790055
AN - SCOPUS:70349778666
SN - 0004-3591
VL - 60
SP - 3061
EP - 3071
JO - Arthritis and Rheumatism
JF - Arthritis and Rheumatism
IS - 10
ER -