title: Evidence for bioeffects of LY 139478 on the human pre-osteoclastic cell line FLG 29.1.
abstract: 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 E2) demonstrated that the relative potency of LY 139478 in inhibiting estrogen binding to its receptor was equal to that of 17 beta E2. Significant (p < 0.05) dose-dependent inhibition of cell growth was induced by LY 139478 at 10 nM, 100 nM and 1 microM. Calcitonin-induced cAMP accumulation was significantly increased by low (1 pM) and high (1 microM) doses of both 17 beta E2 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 E2 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.
authors.affiliation: Department of Clinical Physiopathology, University of Florence, School of Medicine, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Fiorelli
authors.forename: F
authors.initials: F
authors.lastname: Gori
authors.forename: U
authors.initials: U
authors.lastname: Frediani
authors.forename: A M
authors.initials: AM
authors.lastname: Morelli
authors.forename: A
authors.initials: A
authors.lastname: Falchetti
authors.forename: S
authors.initials: S
authors.lastname: Benvenuti
authors.forename: L
authors.initials: L
authors.lastname: Masi
authors.forename: M L
authors.initials: ML
authors.lastname: Brandi
mesh_terms: D001854:Bone Marrow Cells; D002116:Calcitonin / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D000242:Cyclic AMP / Q000032:analysis; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004958:Estradiol / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology*; D000091344:Filaggrin Proteins; D006801:Humans; D015850:Interleukin-6 / Q000032:analysis; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D004965:Estrogen Antagonists; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D015850:Interleukin-6; D011759:Pyrrolidines; D013876:Thiophenes; D004958:Estradiol; C025430:LY 117018; D002116:Calcitonin; D000242:Cyclic AMP