Heparin is essential for the storage of specific granule proteases in mastcells

All mammals produce heparin, a negatively charged glycosaminoglycan that is a major constituent of the secretory granules of mast cells which are foun d in the peritoneal cavity and most connective tissues. Although heparin is one of the most studied molecules in the body, its physiological function has yet to be determined. Here we describe transgenic mice, generated by di srupting the N-deacetylase/N-sulphotransferase-2 gene(1,2), that cannot exp ress fully sulphated heparin, The mast cells in the skeletal muscle that no rmally contain heparin lacked metachromatic granules and failed to store ap preciable amounts of mouse mast-cell protease (mMCP)-4, mMCP-5 and carboxyp eptidase A (mMC-CPA), even though they contained substantial amounts of mMC P-7, We developed mast cells from the bone marrow of the transgenic mice. A lthough these cultured cells contained high levels of various protease tran scripts and had substantial amounts of mMCP-6 protein in their granules, th ey also failed to express mMCP-5 and mMC-CPA, Our data show that heparin co ntrols, through a post-translational mechanism, the levels of specific cass ettes of positively charged proteases inside mast cells.