title: Kruppel-like factor 4 attenuates osteoblast formation, function, and cross talk with osteoclasts.
abstract: Osteoblasts not only control bone formation but also support osteoclast differentiation. Here we show the involvement of Kruppel-like factor 4 (KLF4) in the differentiation of osteoclasts and osteoblasts. KLF4 was down-regulated by 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) in osteoblasts. Overexpression of KLF4 in osteoblasts attenuated 1,25(OH)2D3-induced osteoclast differentiation in co-culture of mouse bone marrow cells and osteoblasts through the down-regulation of receptor activator of nuclear factor κB ligand (RANKL) expression. Direct binding of KLF4 to the RANKL promoter repressed 1,25(OH)2D3-induced RANKL expression by preventing vitamin D receptor from binding to the RANKL promoter region. In contrast, ectopic overexpression of KLF4 in osteoblasts attenuated osteoblast differentiation and mineralization. KLF4 interacted directly with Runx2 and inhibited the expression of its target genes. Moreover, mice with conditional knockout of KLF4 in osteoblasts showed markedly increased bone mass caused by enhanced bone formation despite increased osteoclast activity. Thus, our data suggest that KLF4 controls bone homeostasis by negatively regulating both osteoclast and osteoblast differentiation.
authors.affiliation: Department of Pharmacology, Medical Research Center for Gene Regulation and BK21 plus, Chonnam National University Medical School, Gwangju 501-746, Korea.
authors.forename: Jung Ha
authors.initials: JH
authors.lastname: Kim
authors.forename: Kabsun
authors.initials: K
authors.lastname: Kim
authors.forename: Bang Ung
authors.initials: BU
authors.lastname: Youn
authors.forename: Jongwon
authors.initials: J
authors.lastname: Lee
authors.forename: Inyoung
authors.initials: I
authors.lastname: Kim
authors.forename: Hong-In
authors.initials: HI
authors.lastname: Shin
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.forename: Nacksung
authors.initials: N
authors.lastname: Kim
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000166:cytology* / Q000378:metabolism; D002117:Calcitriol / Q000502:physiology; D002450:Cell Communication; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D015536:Down-Regulation; D015870:Gene Expression; D005786:Gene Expression Regulation; D006706:Homeostasis; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000502:physiology*; D010010:Osteoclasts / Q000502:physiology*; D011401:Promoter Regions, Genetic; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D053245:RANK Ligand; D018167:Receptors, Calcitriol; C493716:Runx2 protein, mouse; C505689:Tnfsf11 protein, mouse; D002117:Calcitriol