In osteo- and rheumatoid arthritis, the synovial fluid surrounding chondrocytes contains increased levels of prostaglandin E(2) (PGE(2)), an agent known to elevate intracellular cyclic AMP (cAMP). However, the effect of PGE(2)/cAMP on mRNA expression in chondrocytes is largely unknown. In this report, we assess the effect of the cell-permeable cAMP analog adenosine 8-(4-chloro-phenylthio)-3',5'-cyclic monophosphate (CPT-cAMP) and PGE(2) on mRNA expression in primary neonatal rat chondrocytes. CPT-cAMP decreased type II collagen, link protein, parathyroid hormone/parathyroid hormone-related peptide receptor and alkaline phosphatase, increased glyceraldehyde-3-phosphate dehydrogenase mRNA and lactate efflux, but did not alter type X collagen or aggrecan mRNA. The effect of CPT-cAMP on type II collagen and link protein mRNAs and chondrocyte metabolism were attenuated by the transcriptional inhibitor actinomycin D, indicating that the ability of CPT-cAMP to suppress mRNA expression was not due to alterations in mRNA stability, but were instead likely due to transcriptional mechanisms. CPT-cAMP-treatment induced GSK3 beta phosphorylation and beta-catenin-mediated transcriptional activity. Pharmacological inhibition of GSK3 beta paralleled the effects of CPT-cAMP on type II collagen, link protein and chondrocyte metabolism, suggesting that the effect of CPT-cAMP on chondrocytes may be GSK3 beta/beta-catenin-dependent. The effects of CPT-cAMP on beta-catenin-mediated transcription, cell metabolism and mRNA expression were mimicked by the cAMP-elevating agent PGE(2), providing a physiologically relevant context for our studies. Collectively, these results suggest that agents that elevate cAMP signaling may impair chondrocyte function in conditions such as arthritis.