Estrogen receptor isoform-specific induction of progesterone receptors in human osteoblasts

David J. Rickard, Katrina M. Waters, Terry J. Ruesink, Sundeep Khosla, John A. Katzenellenbogen, Benita S. Katzenellenbogen, B. Lawrence Riggs, Thomas C. Spelsberg

Research output: Contribution to journalArticle

Abstract

Estrogen induction of progesterone receptor (PR) expression may be important to bone physiology because progesterone has been implicated in the control of bone formation and resorption. Although PR gene expression can be induced in osteoblasts by estrogen signaling through the estrogen receptor (ER) α isoform, it is unknown whether the ER-β isoform is involved in this regulation. The effect of estrogen on PR expression was examined in human fetal osteoblast (hFOB) cell lines stably transfected with either ER-α or ER-β. Estrogen treatment of hFOB/ER-α cells induced PR messenger RNA (mRNA) steady-state levels after 24 h and protein levels after 48 h, as established by competitive reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting. Interestingly, no induction of PR expression was observed in the hFOB/ER-β cells during this period. However, PR mRNA was induced progressively after 48 h of treatment with estrogen with maximum levels achieved at 12 days posttreatment. ER protein also was increased after 12 days of treatment. Both A and B isoforms of PR (PRA and PRB) were induced by estrogen in the hFOB/ER-α cells as well as much later in hFOB/ER-β cells. The pure antiestrogen ICI 182, 780 prevented PR induction by estrogen in both cell lines. An ER-β-selective antagonist R, R-tetrahydrochrysene (THC) abolished the induction of PR mRNA in hFOB/ER-β but not in hFOB/ER-α cells, verifying that the response in the former cell line was ER-β-mediated. Transient cotransfection of hFOB cells with ER-α or ER-β together with either a human PRA or PRB promoter linked to a reporter plasmid revealed that although the PRB promoter was stimulated equally by estrogen activation of either ER isoform, PRA was activated preferentially by ER-α. Together, these results show that although estrogen can up-regulate endogenous PR gene expression in osteoblasts via both ER isoforms, ER-α is the predominant inducer.

Original languageEnglish (US)
Pages (from-to)580-592
Number of pages13
JournalJournal of Bone and Mineral Research
Volume17
Issue number4
DOIs
StatePublished - Jan 1 2002

Keywords

  • Estrogen
  • Estrogen receptor isoforms
  • Osteoblasts
  • Progesterone receptor
  • Progesterone receptor promoter

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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  • Cite this

    Rickard, D. J., Waters, K. M., Ruesink, T. J., Khosla, S., Katzenellenbogen, J. A., Katzenellenbogen, B. S., Riggs, B. L., & Spelsberg, T. C. (2002). Estrogen receptor isoform-specific induction of progesterone receptors in human osteoblasts. Journal of Bone and Mineral Research, 17(4), 580-592. https://doi.org/10.1359/jbmr.2002.17.4.580