title: Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate.
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 viaTet1andTet2and promotes preosteoblast differentiation by enhancing extracellular matrix mineralization and the expression of osteoblastic markers (Runx2,Col1a1,Bglap2,Sp7,Atf4, andAlpl). 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 theTet1/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 resorptionin vivo Thus, SFN is a member of a new class of epigenetic compounds that could be considered for novel strategies to counteract osteoporosis.
authors.affiliation: From the Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risks (AUVA) Trauma Center Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria, Department of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, and.
authors.forename: Roman
authors.initials: R
authors.lastname: Thaler
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Maurizi
authors.affiliation: From the Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risks (AUVA) Trauma Center Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Roschger
authors.affiliation: From the Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risks (AUVA) Trauma Center Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria.
authors.forename: Ines
authors.initials: I
authors.lastname: Sturmlechner
authors.affiliation: Department of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, and.
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Khani
authors.affiliation: From the Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risks (AUVA) Trauma Center Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria.
authors.forename: Silvia
authors.initials: S
authors.lastname: Spitzer
authors.affiliation: From the Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risks (AUVA) Trauma Center Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria.
authors.forename: Monika
authors.initials: M
authors.lastname: Rumpler
authors.affiliation: From the Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risks (AUVA) Trauma Center Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria.
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.affiliation: From the Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risks (AUVA) Trauma Center Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Karlic
authors.affiliation: Department of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, and.
authors.forename: Amel
authors.initials: A
authors.lastname: Dudakovic
authors.affiliation: From the Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risks (AUVA) Trauma Center Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria.
authors.forename: Klaus
authors.initials: K
authors.lastname: Klaushofer
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Teti
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy rucci@univaq.it.
authors.forename: Nadia
authors.initials: N
authors.lastname: Rucci
authors.affiliation: From the Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risks (AUVA) Trauma Center Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria, franz.varga@osteologie.at.
authors.forename: Franz
authors.initials: F
authors.lastname: Varga
authors.affiliation: Department of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, and vanwijnen.andre@mayo.edu.
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010024:Osteoporosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010052:Ovariectomy; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000076182:Sp7 Transcription Factor; D013454:Sulfoxides; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: C081452:Atf4 protein, mouse; D050071:Bone Density Conservation Agents; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; D017879:Isothiocyanates; D011518:Proto-Oncogene Proteins; D053245:RANK Ligand; C493716:Runx2 protein, mouse; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D013454:Sulfoxides; C540839:TET1 protein, mouse; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; D051701:Activating Transcription Factor 4; D049308:Dioxygenases; C551914:Tet2 protein, mouse; D053181:Caspase 8; C016766:sulforaphane
keywords: bone; epigenetics; osteoblast; osteoclast; osteoporosis