title: Regulation of osteoblast differentiation by interleukin-11 via AP-1 and Smad signaling.
abstract: Mechanical stress and parathyroid hormone (PTH) are major stimulators, and aging and glucocorticoids excess are important suppressors of osteoblast differentiation. Mechanical stress and PTH stimulate interleukin (IL)-11 expression in cells of osteoblast lineage by enhancing transcription of IL-11 gene via an increase in intracellular Ca²⁺. The elevated Ca²⁺ activates extracellular signal-regulated kinase (ERK) to enhance phosphorylation of cyclic AMP response element-binding protein (CREB), which binds to the fosB gene promoter and enhances ΔFosB expression. ΔFosB dimerizes with JunD on the IL-11 gene promoter to enhance its transcription. Both mechanical stress and PTH also stimulate phosphorylation of Smad1 via an activation of protein kinase Cδ (PKCδ). Phosphorylated Smad1 binds to the IL-11 gene promoter and forms complex with ΔFosB/JunD to further enhance IL-11 gene transcription. The increased IL-11 then suppresses expression of Wnt inhibitors, including Dickkopf 1 (Dkk1) and 2, and enhances Wnt signaling to stimulate osteoblast differentiation and inhibit adipocyte differentiation. The suppression of osteoblast differentiation by aging involves a decrease in IL-11 gene transcription by a reduction in JunD binding to the activator protein (AP)-1 site of the IL-11 gene promoter. Glucocorticoids inhibit transcriptional activation of IL-11 gene by an interaction of glucocorticoid-glucocorticoid receptor (GR) complex with ΔFosB/JunD heterodimer. Thus, factors that enhance osteoblast differentiation stimulate, and those which suppress osteoblast differentiation inhibit IL-11 gene transcription, and IL-11 enhances Wnt signaling by suppressing expression of its inhibitors. These observations are consistent with the notion that IL-11 mediates stimulatory and inhibitory signals of osteoblast differentiation by affecting Wnt signaling.
authors.affiliation: Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Medical Sciences, Tokushima, Japan. toshimat@clin.med.tokushima-u.ac.jp
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Rika
authors.initials: R
authors.lastname: Kuriwaka-Kido
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kondo
authors.forename: Itsuro
authors.initials: I
authors.lastname: Endo
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Kido
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000375:Aging; D000818:Animals; D002454:Cell Differentiation; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017370:Interleukin-11 / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism*; D010012:Osteogenesis; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D017370:Interleukin-11; D051785:Smad Proteins; D018808:Transcription Factor AP-1