title: Sulfuretin promotes osteoblastic differentiation in primary cultured osteoblasts and in vivo bone healing.
abstract: Although sulfuretin, the major flavonoid of Rhus verniciflua Stokes, has a variety of biological actions, its in vitro and in vivo effects on osteogenic potential remain poorly understood. The objective of the present study was to investigate the effects of sulfuretin on in vitro osteoblastic differentiation and the underlying signal pathway mechanisms in primary cultured osteoblasts and on in vivo bone formation using critical-sized calvarial defects in mice. Sulfuretin promoted osteogenic differentiation of primary osteoblasts, with increased ALP activity and mineralization, and upregulated differentiation markers, including ALP, osteocalcin, and osteopontin, in a concentration-dependent manner. The expression levels of Runx2, BMP-2, and phospho-Smad1/5/8 were upregulated by sulfuretin. Moreover, sulfuretin increased phosphorylation of Akt, mTOR, ERK, and JNK. Furthermore, sulfuretin treatment increased mRNA expression of Wnt ligands, phosphorylation of GSK3, and nuclear β-catenin protein expression. In vivo studies with calvarial bone defects revealed that sulfuretin significantly enhanced new bone formation by micro-computed tomography and histologic analysis. Collectively, these data suggest that sulfuretin acts through the activation of BMP, mTOR, Wnt/β-catenin, and Runx2 signaling to promote in vitro osteoblast differentiation and facilitate in vivo bone regeneration, and might be have therapeutic benefits in bone disease and regeneration.
authors.affiliation: Department of Oral Medicine, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Q-Schick
authors.initials: QS
authors.lastname: Auh
authors.affiliation: Department of Oral & Maxillofacial Regeneration, Graduate School, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Kyung-Ran
authors.initials: KR
authors.lastname: Park
authors.affiliation: Department of Oral and Maxillofacial Pathology, School of Dentistry and Research Center for Tooth & Periodontal Regeneration (MRC), Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Hyung-Mun
authors.initials: HM
authors.lastname: Yun
authors.affiliation: Department of Periodontology, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Hyun-Chang
authors.initials: HC
authors.lastname: Lim
authors.affiliation: Department of Oral & Maxillofacial Regeneration, Graduate School, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Ga-Hyun
authors.initials: GH
authors.lastname: Kim
authors.affiliation: Department of Biomedical Chemistry, College of Health and Biomedical Science, Konkuk University, Chung-Ju, Republic of Korea.
authors.forename: Dong-Sung
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Republic of Korea.
authors.forename: Youn-Chul
authors.initials: YC
authors.lastname: Kim
authors.affiliation: Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Republic of Korea.
authors.forename: Hyuncheol
authors.initials: H
authors.lastname: Oh
authors.affiliation: Department of Oral and Maxillofacial Pathology, School of Dentistry and Research Center for Tooth & Periodontal Regeneration (MRC), Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Eun-Cheol
authors.initials: EC
authors.lastname: Kim
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D001861:Bone Regeneration / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D053495:Osteopontin / Q000378:metabolism; D061251:Primary Cell Culture; D012886:Skull / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D060449:Wnt Signaling Pathway / Q000187:drug effects; D055114:X-Ray Microtomography; D051176:beta Catenin / Q000378:metabolism
chemical_list: C525718:BMP2 protein, human; D001572:Benzofurans; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; C495267:CTNNB1 protein, mouse; D050659:Core Binding Factor Alpha 1 Subunit; D005419:Flavonoids; C493716:Runx2 protein, mouse; C506896:Spp1 protein, mouse; D051176:beta Catenin; D015675:Osteocalcin; D053495:Osteopontin; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D000469:Alkaline Phosphatase; C054989:sulfuretin
keywords: Differentiation; In vitro; In vivo; Osteoblasts; Osteogenesis; Signal pathways, Pathology Section