AG-041R, a gastrin/CCK-B antagonist, stimulates chondrocyte proliferation and metabolism in vitro

A newly synthesized compound, AG-041R, 3R-1-(2,2Diethoxyethyl)-3- ((4methyl phenyl) amino-carbonylmethyl)-3-( (4methylphenyl)ureido-indoline-2-one), is a cholecyctokinin-B/gastrin receptor antagonist, but unexpectedly magnifie d cartilage formation in vivo, Indeed, AG-041R is a potentially effective r eagent for the repair of articular cartilage defects. To clarify its effect s on chondrocytes, we studied the proliferation, matrix formation, and gene expression of rabbit primary chondrocytes cultured in type I collagen gel composites with AG-041R, Both proliferation and glycosaminoglycan synthesis were stimulated with 1 muM AG-041R, but suppressed with 10 muM. The ratio of the amounts of two chondroitin sulfate isomers, chondroitin-6-sulfate to chondroitin-4-sulfate tan indicator of cartilage maturation), increased wi th 1 muM but decreased with 10 muM AG-041R, Gene expression analysis showed there was no change in the relative expression levels of chondrocyte marke rs, Type II collagen and Aggrecan, and osteoblast and adipocyte markers, Ty pe I collagen and PPAR gamma, respectively. These findings suggest that ade quate concentrations of AG-041R stimulate proliferation of chondrocytes in the matrix, without changing their differentiated characteristics. (C) 2001 Academic Press.