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Estrogens and selective estrogen receptor modulators differentially antagonize Runx2 in ST2 mesenchymal progenitor cells

Journal article
Authors Y. Amzaleg
J. Ji
D. Kittivanichkul
Anna E Törnqvist
Sara H Windahl
E. Sabag
A. B. Khalid
H. Sternberg
M. West
J. A. Katzenellenbogen
S. A. Krum
N. O. Chimge
D. E. Schones
Y. Gabet
Claes Ohlsson
B. Frenkel
Published in Journal of Steroid Biochemistry and Molecular Biology
Volume 183
Pages 10-17
ISSN 0960-0760
Publication year 2018
Published at Centre for Bone and Arthritis Research
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 10-17
Language en
Keywords Osteoblast, Osteoclast, Alkaline phosphatase, Raloxifene, Lasofoxifene, Puerarin, osteoblast differentiation, androgen receptor, breast-cancer, bone-marrow, postmenopausal women, alpha, osteoporosis, deficiency, cbfa1, gene, Biochemistry & Molecular Biology, Endocrinology & Metabolism
Subject categories Biochemistry and Molecular Biology


Estrogens attenuate bone turnover by inhibiting both osteoclasts and osteoblasts, in part through antagonizing Runx2. Apparently conflicting, stimulatory effects in osteoblast lineage cells, however, sway the balance between bone resorption and bone formation in favor of the latter. Consistent with this dualism, 17 beta-estradiol (E2) both stimulates and inhibits Runx2 in a locus-specific manner, and here we provide evidence for such locus specific regulation of Runx2 by E2 in vivo. We also demonstrate dual, negative and positive, regulation of Runx2-driven alkaline phosphatase (ALP) activity by increasing E2 concentrations in ST2 osteoblast progenitor cells. We further compared the effects of E2 to those of the Selective Estrogen Receptor Modulators (SERMs) raloxifene (ral) and lasofoxifene (las) and the phytoestrogen puerarin. We found that E2 at the physiological concentrations of 0.1-1 nM, as well as ral and las, but not puerarin, antagonize Runx2-driven ALP activity. At >= 10 nM, E2 and puerarin, but not ral or las, stimulate ALP relative to the activity measured at 0.1-1 nM. Contrasting the difference between E2 and SERMs in ST2 cells, they all shared a similar dose-response profile when inhibiting preosteoclast proliferation. That ral and las poorly mimic the locus-and concentration-dependent effects of E2 in mesenchymal progenitor cells may help explain their limited clinical efficacy.

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