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Journal of Bone and Mineral Research, Volume 21, Issue S1, 1 September 2006, Pages S102–S151, https://doi.org/10.1002/jbmr.5650211404
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04 March 2010
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04 March 2010
Published:
04 March 2010
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2006 Abstracts: Twenty‐Eighth Annual Meeting of the American Society for Bone and Mineral Research: Pennsylvania Convention Convention Center Philadelphia, Pennsylvania, USA, September 15–19, 2006, Journal of Bone and Mineral Research, Volume 21, Issue S1, 1 September 2006, Pages S102–S151, https://doi.org/10.1002/jbmr.5650211404
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The Adaptor BCAR1 Is Critical for RANKL‐Stimulated Osteoclast Formation and Mediates Nongenomic Estrogen Inhibition of RANKL Signaling. L. J. Robinson*, B. B. Yaroslavskiy, A. C. Sharrow*, H. C. Blair. Pathology, University of Pittsburgh, Pittsburgh, PA, USA
We studied estrogen effects on RANKL‐stimulated differentiation of human CD14 cells. Estrogen was known to inhibit early RANKL signal transduction and blunt osteoclast formation in murine Raw267.4 cells. The rapidity of the effect, <1 hour, suggested a non‐transcriptional mechanism, but no specifics were known. In CD14 cells, estrogen also inhibited osteoclast differentiation at an early stage, prior to osteoclast marker expression. Annexin V labeling showed this to be unrelated to apoptosis. Further, osteoclast pit formation was suppressed even if estradiol was removed 18 h after RANKL induction, at which time no significant differentiation had occurred. The signalling intermediate BCAR1/pBOC as was known to mediate non‐genomic estrogen effects in human breast cancer cells through a multi‐protein complex involving ERα. Western blotting and immunofluorescence showed that BCAR1 is abundant in human osteoclast precursors. BCAR1 was localized in highly organized cytoplasmic complexes. Coimmunoprecipitation revealed rapid estrogen‐dependent formation of an ERα‐BCAR1 complex that was enhanced by RANKL costimulation, indicating cooperative regulation of BCAR1 by estrogen and RANKL. Estrogen and RANKL‐stimulated complex formation correlated with reduced NF‐κB nuclear translocation. TRAF6, a key second messenger for RANK, precipitated with the ERα‐BCAR1 complex. Thus, BCAR1 interacts with RANKL signaling components, so modulation of BCAR1 by ERα may mediate the effects of estrogen on RANK. This hypothesis suggests that elimination of BCAR1 would abrogate the effect of estrogen on RANK signalling. RNA interference was used to eliminate BCAR1 in CD14 cells. Fluorescently‐labeled siRNA was used to verify cell uptake, and Western blots to confirm BCAR1 suppression. Control siRNA in parallel cultures verified specificity. Suppression of BCAR1 did eliminate estrogen inhibition of NF‐κB translocation, consistent with BCAR1‐mediation of nongenomic estrogen effects. In addition, absence of BCAR1 in itself impaired RANKL‐stimulated NF‐κB translocation, implying that BCAR1 is involved in RANKL signaling in the absence of estrogen. Studies of osteoclast differentiation after suppression of BCAR1 confirmed an important role for BCAR1 in osteoclast formation: Osteoclastic differentiation of CD14 cells and their survival were severely impaired, with multinucleation and TRAP expression at 4 and 7 days essentially eliminated. Our results implicate BCAR1 in nongenomic estrogen effects on pre‐osteoclasts, and further reveal the critical importance of BCAR1 in RANKL‐induced human osteoclast differentiation.
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2006 Abstracts: Twenty‐Eighth Annual Meeting of the American Society for Bone and Mineral Research: Pennsylvania Convention Convention Center Philadelphia, Pennsylvania, USA, September 15–19, 2006 - 24 Hours access
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