EVIDENCE FOR BIOEFFECTS OF LY-139478 ON THE HUMAN PRE-OSTEOCLASTIC CELL-LINE FLG-29.1

LY 139478, the hydrochloride salt of LY 117018, is a member of the nonsteroidal antiestrogens, benzothiophene derivatives, described to be full estrogen agonists in bone acting via an estrogen receptor-mediated mechanism. However, the cellular actions of these compounds on bone remodelling need to be established. To investigate the ''in vitro'' properties of LY 139478 on osteoclast precursors, the human pre-osteoclastic cell line FLG 29.1 was examined for evidence of bioeffects of this compound. Binding studies with tritiated 17 beta-estradiol (17 beta E(2)) demonstrated that the relative potency of LY 139478 in inhibiting estrogen binding to its receptor was equal to that of 17 beta E(2).Significant (p<0.05) dose-dependent inhibition of cell growth was induced by LY 139478 at 10 nM, 100 nM and 1 mu M Calcitonin-induced cAMP accumulation was significantly increased by low (1 pM) and high (1 mu M) doses ofboth 17 beta E(2) and the compound with a dose-dependent response. Differently than estrogen, LY 139478 at high dose significantly reduced IL-6 release by these cells. In addition, pharmacological doses of both 17 beta E(2) and LY 139478 activated apoptotic cell death. These findings show that the benzothiophene-derived LY 139478 acts directly on the human pre-osteoclastic cell line FLG 29.1 as an estrogen agonist. (C) 1995 Academic Press, Inc.