The present study was designed to evaluate the effects of neuropeptide substance 11 (SP) on the formation of osteoclasts via synovial fibroblastic cells. Synovial fibroblastic cells derived from rat knee joint expressed the SP receptor, neurokinin-1 receptor (Nkappa(1)-R). The addition of SP stimulated the proliferation of synovial fibroblastic cells and this effect was inhibited by SP or Nkappa(1)-R antagonists. Increased expression of the receptor activator of nuclear factor kappaB ligand (RANKL) in synovial fibroblastic cells after the addition of SP was demonstrated by reverse transcriptase-polymerase chain reaction and immunofluorescence staining. Osteoprotegerin expression in synovial fibroblastic cells was decreased after incubation with SP. In co-cultures of synovial fibroblastic cells and rat peripheral blood monocytes, SP stimulated osteoclastogenesis. These results suggest that SP in the joint cavity may cause both hypertrophy of the synovium and induction of increased osteoclast formation through the increased expression of RANKL in the synovium. (C) 2004 Elsevier Inc. All rights reserved.