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

Yonatan Amzaleg, Jie Ji, Donlaporn Kittivanichkul, Anna E Törnqvist, Sara Windahl, Elias Sabag, Aysha B. Khalid, Hal Sternberg, Michael West, John A. Katzenellenbogen, Susan Miranda, Nyam Osor Chimge, Dustin E. Schones, Yankel Gabet, Claes Ohlsson, Baruch Frenkel

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Abstract

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, 17ß-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 pre-osteoclast 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.

Original languageEnglish (US)
Pages (from-to)10-17
Number of pages8
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume183
DOIs
StatePublished - Oct 1 2018

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Selective Estrogen Receptor Modulators
Mesenchymal Stromal Cells
Osteoblasts
Estrogens
Alkaline Phosphatase
Bone
Osteoclasts
Phytoestrogens
Bone Remodeling
Bone Resorption
Osteogenesis
Estradiol
Stem Cells
Bone and Bones
Lasofoxifene
Raloxifene Hydrochloride
puerarin

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Estrogens and selective estrogen receptor modulators differentially antagonize Runx2 in ST2 mesenchymal progenitor cells. / Amzaleg, Yonatan; Ji, Jie; Kittivanichkul, Donlaporn; E Törnqvist, Anna; Windahl, Sara; Sabag, Elias; Khalid, Aysha B.; Sternberg, Hal; West, Michael; Katzenellenbogen, John A.; Miranda, Susan; Chimge, Nyam Osor; Schones, Dustin E.; Gabet, Yankel; Ohlsson, Claes; Frenkel, Baruch.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 183, 01.10.2018, p. 10-17.

Research output: Contribution to journalArticle

Amzaleg, Y, Ji, J, Kittivanichkul, D, E Törnqvist, A, Windahl, S, Sabag, E, Khalid, AB, Sternberg, H, West, M, Katzenellenbogen, JA, Miranda, S, Chimge, NO, Schones, DE, Gabet, Y, Ohlsson, C & Frenkel, B 2018, 'Estrogens and selective estrogen receptor modulators differentially antagonize Runx2 in ST2 mesenchymal progenitor cells', Journal of Steroid Biochemistry and Molecular Biology, vol. 183, pp. 10-17. https://doi.org/10.1016/j.jsbmb.2018.05.002
Amzaleg, Yonatan ; Ji, Jie ; Kittivanichkul, Donlaporn ; E Törnqvist, Anna ; Windahl, Sara ; Sabag, Elias ; Khalid, Aysha B. ; Sternberg, Hal ; West, Michael ; Katzenellenbogen, John A. ; Miranda, Susan ; Chimge, Nyam Osor ; Schones, Dustin E. ; Gabet, Yankel ; Ohlsson, Claes ; Frenkel, Baruch. / Estrogens and selective estrogen receptor modulators differentially antagonize Runx2 in ST2 mesenchymal progenitor cells. In: Journal of Steroid Biochemistry and Molecular Biology. 2018 ; Vol. 183. pp. 10-17.
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abstract = "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{\ss}-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 pre-osteoclast 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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AU - Amzaleg, Yonatan

AU - Ji, Jie

AU - Kittivanichkul, Donlaporn

AU - E Törnqvist, Anna

AU - Windahl, Sara

AU - Sabag, Elias

AU - Khalid, Aysha B.

AU - Sternberg, Hal

AU - West, Michael

AU - Katzenellenbogen, John A.

AU - Miranda, Susan

AU - Chimge, Nyam Osor

AU - Schones, Dustin E.

AU - Gabet, Yankel

AU - Ohlsson, Claes

AU - Frenkel, Baruch

PY - 2018/10/1

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N2 - 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, 17ß-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 pre-osteoclast 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.

AB - 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, 17ß-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 pre-osteoclast 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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