REGULATION OF HUMAN MONOCYTE MATRIX METALLOPROTEINASES BY SPARC

SPARC (secreted protein, acidic and rich in cysteine), also called ost eonectin or BM-40, is a collagen-binding glycoprotein secreted by a va riety of cells and is associated with functional responses involving t issue remodeling, cell movement and proliferation. Because SPARC and m onocytes/macrophages are prevalent at sites of inflammation and remode ling in which there is connective tissue turnover, we examined the eff ect of SPARC on monocyte matrix metalloproteinase (MMP) production. Tr eatment of human peripheral blood monocytes with SPARC stimulated the production of gelatinase B (MMP-9) and interstitial collagenase (MMP-1 ). Experiments with synthetic peptides indicated that peptide 3.2, bel onging to the alpha helical domain III of SPARC, is the major peptide mediating the MMP production by monocytes. SPARC and peptide 3.2 were also shown to induce prostaglandin synthase (PGHS)-2 as determined by Western and Northern blot analyses. The increase in PGHS-2 stimulated by SPARC or peptide 3.2 correlated with substantially elevated levels of prostaglandin E-2 (PGE(2)) and other arachidonic acid metabolites a s measured by radioimmunoassay and high performance liquid chromatogra phy (HPLC), respectively. Moreover, the synthesis of MMP was dependent on the generation of PGE(2) by PGHS-2, since indomethacin inhibited t he production of these enzymes and their synthesis was restored by add ition of exogenous PGE(2) or dibutyryl cAMP (Bt(2)cAMP). These results demonstrate that SPARC might play a significant role in the modulatio n of connective tissue turnover due to its stimulation of PGHS-2 and t he subsequent release of PGE(2), a pathway that leads to the productio n of MMP by monocytes. (C) 1997 Wiley-Liss, Inc.(+)