A newly synthesized compound, AG-041R, 3R-1-(2,2Diethoxyethyl)-3-((4methylphenyl) amino-carbonylmethyl)-3-((4methylphenyl)ureido-indoline-2-one), is a cholecyctokinin-B/gastrin receptor antagonist, but unexpectedly magnified cartilage formation in vivo. Indeed, AG-041R is a potentially effective reagent for the repair of articular cartilage defects. To clarify its effects 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 microM AG-041R, but suppressed with 10 microM. The ratio of the amounts of two chondroitin sulfate isomers, chondroitin-6-sulfate to chondroitin-4-sulfate (an indicator of cartilage maturation), increased with 1 microM but decreased with 10 microM AG-041R. Gene expression analysis showed there was no change in the relative expression levels of chondrocyte markers, Type II collagen and Aggrecan, and osteoblast and adipocyte markers, Type I collagen and PPARgamma, respectively. These findings suggest that adequate concentrations of AG-041R stimulate proliferation of chondrocytes in the matrix, without changing their differentiated characteristics.

中文翻译：

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胃泌素/ CCK-B拮抗剂AG-041R在体外刺激软骨细胞增殖和代谢。

新合成的化合物AG-041R，3R-1-（2,2二乙氧基乙基）-3-（（4-甲基苯基）氨基-羰基甲基）-3-（（4-甲基苯基）脲基-吲哚啉-2-一）是胆囊收缩素B /胃泌素受体拮抗剂，但出乎意料地放大了体内的软骨形成。实际上，AG-041R是修复关节软骨缺损的潜在有效试剂。为了阐明其对软骨细胞的作用，我们研究了在具有AG-041R的I型胶原凝胶复合物中培养的兔原代软骨细胞的增殖，基质形成和基因表达。用1 microM AG-041R刺激增殖和糖胺聚糖合成，但用10 microM抑制。两种硫酸软骨素异构体的数量之比：6-硫酸软骨素与4-硫酸软骨素（软骨成熟的指标），AG-041R增加了1 microM，但增加了10 microM。基因表达分析表明，软骨细胞标记物，II型胶原蛋白和Aggrecan的相对表达水平没有变化，成骨细胞和脂肪细胞标记物，I型胶原蛋白和PPARgamma的相对表达水平没有变化。这些发现表明适当浓度的AG-041R刺激了基质中软骨细胞的增殖，而没有改变它们的分化特征。