REGULATION OF OSTEOPROTEGERIN MESSENGER-RNA LEVELS BY PROSTAGLANDIN E-2 IN HUMAN BONE-MARROW STROMA CELLS

The recently cloned osteoclastogenesis inhibitory factor, or osteoprot egerin (OPG), has been shown to be a potent inhibitor of osteoclast fo rmation. The inhibition is believed to be mediated through specific bi nding of OPG; to a cell surface ligand on osteoblastic stromal cells. In this report we have studied the effect of the bone resorbing agent prostaglandin E-2 (PGE(2)) on OPG mRNA levels in primary cultures of h uman bone marrow stroma cells (hBMSC). PGE(2) dose- and time-dependent ly down-regulated the mRNA levels of OPG, as measured by RNAse protect ion assay. After 4 hours of stimulation with 1 mu M PGrE(2), OPG mRNA levels were significantly decreased. The inhibitory effect was seen at and above 1 nM of PGE(2). To elucidate whether the OPG mRNA levels ar e regulated via the proteinkinase A and/or the proteinkinase C pathway s we stimulated cells with either forskolin (FSK) or phorbolic ester ( PDbu) respectively. FSK (10 mu M) decreased OPG mRNA levels to 50 % of control, whereas PE (10 nM) upregulated the mRNA levels to 250 % of c ontrol, These data show that PGE2 down-regulates the expression of OPG ; mRNA in hBMSC, probably via an increase in cAMP. This mechanism migh t be involved in PGE(2)-induced bone resorption. (C) 1998 Academic Pre ss.