Estrogens and androgens inhibit association of RANKL with the pre-osteoblast membrane through post-translational mechanisms

Anthony Martin, Jiali Yu, Jian Xiong, Aysha B. Khalid, Benita Katzenellenbogen, Sung Hoon Kim, John A. Katzenellenbogen, Suchinda Malaivijitnond, Yankel Gabet, Susan A. Krum, Baruch Frenkel

Research output: Contribution to journalArticle

Abstract

We have recently demonstrated that RUNX2 promoted, and 17β-Estradiol (E2) diminished, association of RANKL with the cell membrane in pre-osteoblast cultures. Here we show that, similar to E2, dihydrotestosterone (DHT) diminishes association of RANKL, and transiently transfected GFP-RANKL with the pre-osteoblast membrane without decreasing total RANKL mRNA or protein levels. Diminution of membrane-associated RANKL was accompanied with marked suppression of osteoclast differentiation from co-cultured pre-osteoclasts, even though DHT increased, not decreased, RANKL concentrations in pre-osteoblast conditioned media. A marked decrease in membrane-associated RANKL was observed after 30 min of either E2 or DHT treatment, and near-complete inhibition was observed by 1 hr, suggesting that the diminution of RANKL membrane association was mediated through non-genomic mechanisms. Further indicating dispensability of nuclear action of estrogen receptor, E2-mediated inhibition of RANKL membrane association was mimicked by an estrogen dendrimer conjugate (EDC) that cannot enter the cell nucleus. Finally, the inhibitory effect of E2 and DHT on RANKL membrane association was counteracted by the MMP inhibitor NNGH, and the effect of E2 (and not DHT) was antagonized by the Src inhibitor SU6656. Taken together, these results suggest that estrogens and androgens inhibit osteoblast-driven osteoclastogenesis through non-genomic mechanism(s) that entail, MMP-mediated RANKL dissociation from the cell membrane.

Original languageEnglish (US)
Pages (from-to)3798-3807
Number of pages10
JournalJournal of Cellular Physiology
Volume232
Issue number12
DOIs
StatePublished - Dec 2017

Keywords

  • MMP
  • RANKL presentation
  • Src
  • membrane-initiated estrogen signaling
  • sex steroids

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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    Martin, A., Yu, J., Xiong, J., Khalid, A. B., Katzenellenbogen, B., Kim, S. H., Katzenellenbogen, J. A., Malaivijitnond, S., Gabet, Y., Krum, S. A., & Frenkel, B. (2017). Estrogens and androgens inhibit association of RANKL with the pre-osteoblast membrane through post-translational mechanisms. Journal of Cellular Physiology, 232(12), 3798-3807. https://doi.org/10.1002/jcp.25862