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

Yonatan Amzaleg1, Jie Ji2, Donlaporn Kittivanichkul3

  • 1Center of Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA; Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.

The Journal of Steroid Biochemistry and Molecular Biology
|May 12, 2018
PubMed

Insights

Estrogen

Area of Science:

  • Bone biology
  • Endocrinology
  • Molecular signaling

Background:

  • Estrogens play a dual role in bone turnover, affecting both bone resorption and formation.
  • Estrogen's effects are partly mediated through the transcription factor Runx2.
  • Understanding estrogen's complex regulation of bone cells is crucial for developing effective osteoporosis therapies.

Purpose of the Study:

  • To investigate the locus-specific and concentration-dependent effects of 17ß-estradiol (E2) on Runx2 activity in osteoblast progenitor cells.
  • To compare the effects of E2 with Selective Estrogen Receptor Modulators (SERMs) and a phytoestrogen on Runx2-driven alkaline phosphatase (ALP) activity and pre-osteoclast proliferation.
  • To elucidate the mechanisms underlying the differential efficacy of SERMs in mimicking estrogen's effects on bone.

Main Methods:

  • In vitro studies using ST2 osteoblast progenitor cells.
  • Measurement of Runx2-driven alkaline phosphatase (ALP) activity at varying concentrations of E2, SERMs (raloxifene, lasofoxifene), and puerarin.
  • Assessment of pre-osteoclast proliferation inhibition by E2, SERMs, and puerarin.

Main Results:

  • E2 exhibited dual regulation of Runx2-driven ALP activity in a concentration-dependent manner.
  • Physiological E2 concentrations (0.1-1 nM), raloxifene, and lasofoxifene inhibited ALP activity, while higher E2 concentrations (≥10 nM) and puerarin stimulated it.
  • E2, SERMs, and puerarin all inhibited pre-osteoclast proliferation, but SERMs did not replicate E2's complex effects on osteoblast progenitor cells.

Conclusions:

  • E2 regulates Runx2 activity in a locus- and concentration-dependent manner in osteoblast progenitor cells.
  • SERMs like raloxifene and lasofoxifene partially mimic E2's effects but fail to replicate its nuanced regulation of osteoblast function.
  • The differential effects of E2 and SERMs on mesenchymal progenitor cells may explain the limited clinical efficacy of SERMs in certain contexts.
Keywords:
Alkaline phosphataseLasofoxifeneOsteoblastOsteoclastPuerarinRaloxifene

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