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Estrogen Inhibits RANKL-stimulated Osteoclastic Differentiation of Human Monocytes through Estrogen and RANKL-regulated Interaction of Estrogen Receptor-α with BCAR1 and Traf6
- Publication Year :
- 2009
-
Abstract
- The effects of estrogen on osteoclast survival and differentiation were studied using CD14-selected mononuclear osteoclast precursors from peripheral blood. Estradiol at approximately 1 nM reduced RANKL-dependent osteoclast differentiation by 40-50%. Osteoclast differentiation was suppressed 14 days after addition of RANKL even when estradiol was withdrawn after 18 h. In CD14+ cells apoptosis was rare and was not augmented by RANKL or by 17-beta-estradiol. Estrogen receptor-alpha (ERalpha) expression was strongly down-regulated by RANKL, whether or not estradiol was present. Mature human osteoclasts thus cannot respond to estrogen via ERalpha. However, ERalpha was present in CD14+ osteoclast progenitors, and a scaffolding protein, BCAR1, which binds ERalpha in the presence of estrogen, was abundant. Immunoprecipitation showed rapid (approximately 5 min) estrogen-dependent formation of ERalpha-BCAR1 complexes, which were increased by RANKL co-treatment. The RANKL-signaling intermediate Traf6, which regulates NF-kappaB activity, precipitated with this complex. Reduction of NF-kappaB nuclear localization occurred within 30 min of RANKL stimulation, and estradiol inhibited the phosphorylation of IkappaB in response to RANKL. Inhibition by estradiol was abolished by siRNA knockdown of BCAR1. We conclude that estrogen directly, but only partially, curtails human osteoclast formation. This effect requires BCAR1 and involves a non-genomic interaction with ERalpha.
- Subjects :
- musculoskeletal diseases
medicine.medical_specialty
medicine.drug_class
Cell Survival
Cellular differentiation
Lipopolysaccharide Receptors
Osteoclasts
Biology
Article
Monocytes
Osteoclast
Internal medicine
medicine
Animals
Humans
RNA, Small Interfering
Estrogen receptor beta
Cells, Cultured
TNF Receptor-Associated Factor 6
RANK Ligand
Estrogen Receptor alpha
NF-kappa B
Cell Differentiation
Estrogens
Cell Biology
Endocrinology
medicine.anatomical_structure
Crk-Associated Substrate Protein
Estrogen
RANKL
biology.protein
Female
Signal transduction
Estrogen receptor alpha
hormones, hormone substitutes, and hormone antagonists
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....e47985ba27c2861dff8cd61a47fbeca5