Estrogen Potentiates the Combined Effects of Transforming Growth Factor-β and Tumor Necrosis Factor-α on Adult Human Osteoblast-like Cell Prostaglandin E2 Biosynthesis

Abstract

Reports that estrogen treatment modulates arachidonic acid metabolism by bone and bone cells are found in the literature. However, conflicting indications of the relationship that exists between estrogen and arachidonic acid metabolism emerge from the analysis of those reports. The present studies were undertaken to determine if estrogen effected the production of prostaglandins (PG) in human osteoblast-like (hOB) cell cultures derived from adults, under basal or cytokine-stimulated conditions. A 48-hour estrogen pretreatment did not modify hOB cell PG biosynthesis on a qualitative basis, and PGE 2 formation predominated under all tested conditions. Estrogen pretreatment did lead to increased PGE 2 production in specimens stimulated conjointly with transforming growth factor-β 1 and tumor necrosis factor-α(p < 0.001). No changes in PGE 2 production were observed in estrogen pretreated specimens stimulated singly with either tested cytokine, nor in samples in which either TGFβ or TNF was replaced by interleukin-1β. Anti-estrogen (ICI 164,384) inclusion prevented the estrogen-dependent increase in PGE 2 production in the TGFβ plus TNF-stimulated samples. These results suggest that an estrogen effect on bone cell prostaglandin biosynthesis may be most evident and significant under conditions in which the cells are exposed to multiple osteotropic cytokines, a condition that applies during the bone remodeling process. KeywordsCyclooxygenase; Cytokine; Remodeling; Phospholipase; Anti-estrogen The mechanism(s) through which estrogen modulates bone biology remains incompletely defined despite numerous studies over several decades [1,2,3]. Effects of the sex steroid on bone may not be attributable to a single, dramatic response to treatment that is easily demonstrated; the bone-sparing effects of estrogen may, instead, reflect a montage of several modest changes that cumulatively act to maintain bone mass. It has been reported that estrogen may influence the cellular composition of bone by appropriately altering the apoptosis characteristics of osteoblasts and osteoclasts [4,5,6]. The release of osteotropic cytokines may be sensitive to estrogen modulation, with osteoblastic cell biosynthesis of interleukin-1 (IL-1), interleukin-6, osteoprotegerin, and transforming growth factor-β (TGFβ), among others, cited as changing following estrogen administration [7,8,9,10,11].Correspondence to: P. E. Keeting, pkeeting@mail.wvu.edu. NIH Public Access Author ManuscriptCalcif Tissue Int. Author manuscript; available in PMC 2010 October 20. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe present report examines the effects of estrogen on the elaboration of prostaglandin E 2 (PGE 2 ) by adult human osteoblast-like (hOB) cell cultures variously stimulated by TGFβ, tumor necrosis factor-α (TNF), or IL-1β, cytokines that do increase prostaglandin biosynthesis by hOB cells [12]. Each of these cytokines are products of osteoblastic cells that mediate bone biology in an autocrine/paracrine manner [13,1...

Osteotropic cytokines mediate human osteoblast-like cell eicosanoid production

“…Previous work reported from this laboratory (Xu et al, 1997) demonstrated that TGFβ and TNFα can independently elevate the levels of COX-2 mRNA resulting in increased formation of PGE 2 . When both cytokines were added to specimens concurrently, the independent stimulation of hOB cell COX-2 mRNA levels, protein levels, and prostaglandin biosynthesis was further elevated (Xu et al, 1997;Secreto et al, 2003). Some researchers have reported that TGFβ can stimulate COX-2 mRNA expression in MC3T3-E1 cells (Pilbeam et al, 1997).…”