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J Cell Physiol. 2017 Dec;232(12):3798-3807. doi: 10.1002/jcp.25862. Epub 2017 May 11.

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

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Department of Biochemistry and Molecular Medicine , Keck School of Medicine, University of Southern California, Los Angeles, California.
Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California.
Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, Tennessee.
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois.
Faculty of Science, Department of Biology, Chulalonkorn University, Bangkok, Thailand.
Sackler Faculty of Medicine, Departments of Anatomy and Anthropology and Orthopedic Surgery, Tel Aviv University, Tel Aviv, Israel.
Department of Orthopedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California.


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.


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

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