Numbers of growth factors expressed in the synovium deeply impact on the pathology of rheumatoid arthritis (RA). The WISP family was identified as growth factors, which are upregulated by WNT signaling. In the present study, we investigated expression pattern and regulatory mechanisms of WISPS in the synovium in patients with RA and osteoarthritis (OA). Among three members of WISP family, WISP2 mRNA was only preferentially detected in RA synovium by RT-PCR. WISP2 expression was immunohistochemically identified in RA fibroblasts in an extensive fibrotic area. WNT signaling-activated (s/a beta-catenin-expressing) synovial fibroblasts upregulated WISP2 at 2.9-fold, but inactivated (Delta beta-catenin-expressing) cells downregulated the expression. Quantitative RT-PCR demonstrated that WISP2 expression was increased upon 17-beta-estradiol stimulation and synergistically enhanced by WNT signaling. These data demonstrate that the expression of WISP2 is synergistically upregulated in RA synovial fibroblasts by estrogen and WNT pathways, and suggest an involvement in the pathology of the disease. (c) 2005 Elsevier Inc. All rights reserved.