Previous study showed that synovial fibroblasts derived from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) express β-preprotachykinin (PPT)-A mRNA and release substance P (SP). In this study, we examined the presence of an isoform of PPT-A mRNA in synovial and normal skin fibroblasts by reverse transcription-polymerase chain reaction (RT-PCR) analysis. RA synovial fibroblasts, but not OA synovial and skin fibroblasts, expressed α-isoform PPT-A mRNA together with β-PPT-A mRNA. However, expression of γ- and δ-PPT mRNAs was not observed in synovial and skin fibroblasts. Levels of both α- and β-PPT-A mRNAs were increased in RA fibroblasts treated with transforming growth factor (TGF)-β and basic fibroblast growth factor (bFGF). Treatment with TGF-β and bFGF strongly increased the expression of α- and β-PPT-A mRNAs compared to the individual treatment. Peak levels of α-PPT-A mRNA were reached at 8h whereas those of β-PPT-A mRNA were maximal at 12h after treatment with TGF-β and bFGF. These findings suggest that SP production by synovial fibroblasts in RA is regulated through signaling pathways that lead to the generation of both α- and β-PPT-A mRNAs.