Effects of dioxin and estrogen on collagenase-3 in UMR 106-01 osteosarcomacells

Since estrogen is important in preventing osteoporosis in postmenopausal wo men and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an estrogen antagonis t in reproductive tissues, we investigated the effects of 17 beta -estradio l (E-2) and TCDD on collagenase-3 secretion using parathyroid hormone (PTH) -stimulated UMR 106-01 cells, a rat osteoblastic osteosarcoma cell line. Wh ereas E-2 or TCDD had no effect on UMR cells in the absence of PTH, cells g rown in the presence of 10(-7) M PTH, which induces a dramatic 30-fold incr ease in collagenase-3 secretion, surprisingly demonstrated a further stimul ation of collagenase-3 secretion in the presence of TCDD or E-2. However, t he potentiating response was biphasic; i.e., at higher concentrations of E- 2 or TCDD, there was no enhancement of the PTH effect, PTH induces multiple effects on UMR cells, including inducing collagenase-3 mRNA transcription and regulating its extracellular abundance through a specific receptor and endocytosis. Thus, we investigated the ability of TCDD or E-2 to stimulate the induction of collagenase-3 mRNA using Northern analysis, as previously reported, PTH dose dependently induced collagenase-3 mRNA after 4 h of trea tment, There was little effect of TCDD or E-2 on PTH-induced levels of coll agenase-3 mRNA. These data could not account for the final effects on secre ted collagenase-3, We postulated that low concentrations of E-2 and TCDD ma y downregulate the collagenase-3 endocytotic two-step receptor-mediated pro cess that includes the LDL-receptor-related protein to enhance the effects of PTH. However, this was not the case. Therefore, we conclude that low con centrations of TCDD and estrogen alter translation or secretion of PTH-stim ulated collagenase-3. (C) 2000 Academic Press.