Estradiol rapidly inhibits osteoclastogenesis and RANKL expression in bone marrow cultures in postmenopausal women: a pilot study.
We examined RANKL expression and OCL formation in cultured bone marrow cells from eight postmenopausal women in response to E(2). E(2) treatment inhibited the ability of hematopoietic cells to form OCLs in response to RANKL, and decreased RANKL production. These changes are likely involved in the ability of E(2) to influence the development of osteoporosis.


BACKGROUND
Estrogen (E(2)) deficiency at menopause increases osteoclast (OCL) formation and bone resorption, predisposing women to osteoporosis. We examined receptor activator of NF-kappa B-ligand (RANKL) expression and in vitro OCL formation in cultured bone marrow cells from eight postmenopausal women before and after 3 weeks of E(2) therapy and three untreated premenopausal women.


METHODS
TRAP staining and resorption pit assay determined OCL number and function. Flow cytometry measured the distribution of marrow cell types and expression of RANKL in the macrophage-enriched fraction (R1) and a lymphocyte-enriched fraction (R2).


RESULTS
RANKL (3-100 ng/ml) produced a dose-dependent increase in in vitro OC formation and E(2) therapy significantly (p < 0.01) inhibited OCL formation by 33 to 50%. A small proportion of marrow cells bound anti- RANKL Ab (0.2-4.3%). There was no effect of E(2) on the percentage of cells binding the anti-RANKL Ab in the R1 fraction. In the R2 fraction E(2) treatment decreased the percentage of cells binding anti-RANKL Ab by 68 +/- 9% (p < 0.01).


CONCLUSIONS
Three weeks of E(2) treatment had a dual action. It inhibited the ability of hematopoietic cells to form OCLs in response to RANKL, and decreased the production of RANKL in cells of the bone marrow. The observed changes in the osteoclastic potential of bone marrow cells are likely involved in the ability of E(2) to regulate bone mass and influence the development of osteoporosis.
Taxel
P
P
Department of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-5456, USA. taxel@nso.uchc.edu
Kaneko
H
H
Lee
S-K
SK
Aguila
H L
HL
Raisz
L G
LG
Lorenzo
J A
JA
D000328:Adult; D015992:Body Mass Index; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008875:Middle Aged; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D010865:Pilot Projects; D017698:Postmenopause / Q000378:metabolism / Q000502:physiology*; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology
D053245:RANK Ligand; C505688:TNFSF11 protein, human; D004958:Estradiol; D016173:Macrophage Colony-Stimulating Factor