Anabolic and antiresorptive modulation of bone homeostasis by the epigenetic modulator sulforaphane, a naturally occurring isothiocyanate

Roman Thaler, Antonio Maurizi, Paul Roschger, Ines Sturmlechner, Farzaneh Khani, Silvia Spitzer, Monika Rumpler, Jochen Zwerina, Heidrun Karlic, Amel Dudakovic, Klaus Klaushofer, Anna Teti, Nadia Rucci, Franz Varga, Andre J van Wijnen

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Bone degenerative pathologies like osteoporosis may be initiated by age-related shifts in anabolic and catabolic responses that control bone homeostasis. Here we show that sulforaphane (SFN), a naturally occurring isothiocyanate, promotes osteoblast differentiation by epigenetic mechanisms. SFN enhances active DNA demethylation via Tet1 and Tet2 and promotes preosteoblast differentiation by enhancing extracellular matrix mineralization and the expression of osteoblastic markers (Runx2, Col1a1, Bglap2, Sp7, Atf4, and Alpl). SFN decreases the expression of the osteoclast activator receptor activator of nuclear factor-κB ligand (RANKL) in osteocytes and mouse calvarial explants and preferentially induces apoptosis in preosteoclastic cells via up-regulation of the Tet1/Fas/Caspase 8 and Caspase 3/7 pathway. These mechanistic effects correlate with higher bone volume (∼20%) in both normal and ovariectomized mice treated with SFN for 5 weeks compared with untreated mice as determined by microcomputed tomography. This effect is due to a higher trabecular number in these mice. Importantly, no shifts in mineral density distribution are observed upon SFN treatment as measured by quantitative backscattered electron imaging. Our data indicate that the food-derived compound SFN epigenetically stimulates osteoblast activity and diminishes osteoclast bone resorption, shifting the balance of bone homeostasis and favoring bone acquisition and/or mitigation of bone resorption in vivo. Thus, SFN is a member of a new class of epigenetic compounds that could be considered for novel strategies to counteract osteoporosis.

Original languageEnglish (US)
Pages (from-to)6754-6771
Number of pages18
JournalJournal of Biological Chemistry
Volume291
Issue number13
DOIs
StatePublished - Mar 25 2016

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Thaler, R., Maurizi, A., Roschger, P., Sturmlechner, I., Khani, F., Spitzer, S., Rumpler, M., Zwerina, J., Karlic, H., Dudakovic, A., Klaushofer, K., Teti, A., Rucci, N., Varga, F., & van Wijnen, A. J. (2016). Anabolic and antiresorptive modulation of bone homeostasis by the epigenetic modulator sulforaphane, a naturally occurring isothiocyanate. Journal of Biological Chemistry, 291(13), 6754-6771. https://doi.org/10.1074/jbc.M115.678235