Synovial tissues from 3 RA, 3 OA patients and 5 normal joints were selected according to their disease-characteristic immunhistochemical findings and to their expression of high versus low levels of inflammatory (IL-1β, TNF-α) and destructive markers (MMP-1, MMP-3) as determined by semiquantitative RT-PCR. Pooled mRNA from RA, OA and normal tissues was transcribed, digested by a 4-base-cutter, ligated to adapter-primers and amplified to form representational amplicons. Subtractive hybridizations were performed by different protocols: 1. the OA amplicon (driver) was subtracted from the RA representation (tester); 2. the RA (driver) from the ND (tester) and 3. the ND (driver) from the OA rep-resentaion (tester). Using primers specific for the corresponding tester, the difference-products were selectively amplified, cloned, sequenced and compared to published sequences in the Genebank. Differential expression of identified genes was validated by semiquantitative RT-PCR.