MAST-CELL REGULATION OF HUMAN ENDOMETRIAL MATRIX METALLOPROTEINASES -A MECHANISM UNDERLYING MENSTRUATION

Endometrial matrix metalloproteinases (MMPs), which increase dramatica lly at menstruation, are purported to cause the focal tissue breakdown at menstruation, but how their expression or activation is locally re gulated is unknown. Mast cell activation occurs within perimenstrual e ndometrium, and we postulated that mast cell products would regulate e ndometrial MMPs. We have examined the interaction between human mast c ells and endometrial stromal cells with regard to MMP production and a ctivation. The human mast cell line (HMC-1) in coculture with stromal cells stimulated stromal cell proMMP-1 and proMMP-3, and to a lesser e xtent proMMP-2 production, with increasing stimulation as mast cell nu mber increased. Mast cell-conditioned medium also increased both prote in and mRNA for stromal proMMP-1 and proMMP-3, this being abrogated by preadsorption of mast cell-conditioned medium with antisera to interl eukin-1 and tumor necrosis factor alpha. Mast cell-conditioned medium added to stromal cell culture medium in vitro along with added heparin (which stabilizes tryptase activity) resulted in the appearance of mo lecular weight forms indicative of active MMP-3 and MMP-1. Thus activa ted mast cells within the endometrium prior to menstruation have the p otential to stimulate MMP production by endometrial stromal cells and to initiate precursor activation, and are likely to account for the lo cal nature of endometrial MMP action resulting in foci of tissue break down at menstruation.