title: Effects of estrogen on osteoprogenitor cells and cytokines/bone-regulatory factors in postmenopausal women.
abstract: Decreases in estrogen levels contribute not only to early postmenopausal bone loss but also to bone loss with aging. While estrogen is critical for the maintenance of bone formation, the mechanism(s) of this effect remain unclear. Thus, we assessed the effects of 4months of transdermal estradiol treatment (0.05mg/day) of postmenopausal women as compared to no treatment (n=16 per group) on the expression of genes in pre-specified pathways in freshly isolated bone marrow osteoprogenitor cells (hematopoietic lineage [lin]-/Stro1+). We also evaluated whether estrogen treatment modulated peripheral blood or bone marrow plasma levels of the Wnt antagonists, sclerostin and DKK1, as well as serotonin, OPG, RANKL, adiponectin, oxytocin, and inflammatory cytokines (TNFα, IL-1β, and IL-6), as each of these molecules have recently been shown to play an important role in regulating osteoblast function and/or being responsive to estrogen. We observed a significant decrease in the expression of several proliferation markers (cyclin B1, cyclin E1, E2F1) and increase in adhesion molecules (N-cadherin) in bone marrow lin-/Stro1+ cells from estrogen-treated compared to control women. None of the peripheral blood or bone marrow plasma marker levels differed between the two groups, with the exception of sclerostin levels, which were significantly lower in the estrogen-treated as compared to the control women in peripheral serum (by 32%, P=0.009) and in bone marrow plasma (by 34%, P=0.017). There were significant differences in bone marrow versus peripheral plasma levels of several factors: sclerostin and OPG levels were higher in bone marrow as compared to peripheral plasma, whereas serotonin and adiponectin levels were higher in peripheral as compared to bone marrow plasma. In summary, our data directly assessing possible regulation by estrogen of osteoprogenitor cells in humans indicate that, consistent with previous studies in mice, estrogen suppresses the proliferation of human bone marrow lin-/Stro1+ cells, which likely represent early osteoprogenitor cells. Further animal and human studies are needed to define the role of the changes we observed in mRNAs for adhesion molecules in these cells and in local sclerostin production in bone in mediating the effects of estrogen on bone metabolism in humans.
authors.affiliation: Endocrine Research Unit, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Ulrike I
authors.initials: UI
authors.lastname: Mödder
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Roforth
authors.forename: Kelley
authors.initials: K
authors.lastname: Hoey
authors.forename: Louise K
authors.initials: LK
authors.lastname: McCready
authors.forename: James M
authors.initials: JM
authors.lastname: Peterson
authors.forename: David G
authors.initials: DG
authors.lastname: Monroe
authors.forename: Merry Jo
authors.initials: MJ
authors.lastname: Oursler
authors.forename: Sundeep
authors.initials: S
authors.lastname: Khosla
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D052242:Adiponectin / Q000097:blood; D000368:Aged; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000097:blood / Q000378:metabolism; D001842:Bone and Bones / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood*; D004958:Estradiol / Q000097:blood; D004967:Estrogens / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology*; D004970:Estrone / Q000097:blood; D005260:Female; D005819:Genetic Markers; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D010121:Oxytocin / Q000097:blood; D017698:Postmenopause / Q000097:blood*; D053245:RANK Ligand / Q000097:blood; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D052242:Adiponectin; D019485:Bone Morphogenetic Proteins; D016207:Cytokines; C501126:DKK1 protein, human; D004967:Estrogens; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D053245:RANK Ligand; C422903:SOST protein, human; D014409:Tumor Necrosis Factor-alpha; C437372:interleukin-1 delta; D004970:Estrone; D004958:Estradiol; D010121:Oxytocin