HISTAMINE-STIMULATED PRODUCTION OF MATRIX METALLOPROTEINASE-1 BY HUMAN RHEUMATOID SYNOVIAL FIBROBLASTS IS MEDIATED BY HISTAMINE H-1-RECEPTORS

The purpose of this study was to investigate the role of histamine in human rheumatoid synovial fibroblasts in the production of factors res ponsible for tissue remodelling and cartilage breakdown in rheumatoid arthritis. We examined the effects of histamine of tritiated thymidine incorporation, production of matrix metalloproteinase-1 (MMP-1), hist amine H-1-receptor expression, phosphoinositide metabolism and intrace llular calcium ion concentration ([Ca2+](i)) in human rheumatoid synov ial fibroblasts. Tritiated thymidine incorporation studies demonstrate d that histamine markedly stimulated the proliferation of rheumatoid s ynovial fibroblasts. Immunofluorescence and Northern blot analyses rev ealed that proMMP-1 production was also stimulated by histamine. The l evels of inositol phosphates and [Ca2+](i) in the cells were elevated in response to histamine, indicating that the cells expressed histamin e H-1-receptors; and Northern blot analysis indicated that these H-1-r eceptors were up-regulated by histamine. In in situ hybridization, lar ge amounts of histamine H-1-receptor mRNA were also detected in rheuma toid synovial tissue. These results suggest that the interaction betwe en H-1-receptor expression in rheumatoid synovial fibroblasts and hist amine secretion by mast cells and macrophages in the affected sites is an important event responsible for tissue remodelling and joint destr uction in rheumatoid arthritis.