title: Bone resorption is regulated by cell-autonomous negative feedback loop of Stat5-Dusp axis in the osteoclast.
abstract: Signal transducer and activator of transcription 5 (Stat5) is essential for cytokine-regulated processes such as proliferation, differentiation, and survival in hematopoietic cells. To investigate the role of Stat5 in osteoclasts, we generated mice with an osteoclast-specific conditional deletion of Stat5 (Stat5 conditional knockout [cKO] mice) and analyzed their bone phenotype. Stat5 cKO mice exhibited osteoporosis caused by an increased bone-resorbing activity of osteoclasts. The activity of mitogen-activated protein kinases (MAPKs), in particular extracellular signal-related kinase, was increased in Stat5 cKO osteoclasts, whereas the expression of the MAPK phosphatases dual specificity phosphatase 1 (Dusp1) and Dusp2 was significantly decreased. Interleukin-3 (IL-3) stimulated the phosphorylation and nuclear translocation of Stat5 in osteoclasts, and Stat5 expression was up-regulated in response to receptor activator of nuclear factor κB ligand (RANKL). The results suggest that Stat5 negatively regulates the bone-resorbing function of osteoclasts by promoting Dusp1 and Dusp2 expression, and IL-3 promotes Stat5 activation in osteoclasts.
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Hirose
authors.forename: Hironari
authors.initials: H
authors.lastname: Masuda
authors.forename: Naoto
authors.initials: N
authors.lastname: Tokuyama
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Omata
authors.forename: Takumi
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yasui
authors.forename: Yuho
authors.initials: Y
authors.lastname: Kadono
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
authors.forename: Sakae
authors.initials: S
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015519:Bone Density; D001862:Bone Resorption / Q000235:genetics / Q000503:physiopathology*; D017931:DNA Primers / Q000235:genetics; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000502:physiology*; D006652:Histological Techniques; D020287:In Situ Nick-End Labeling; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007377:Interleukin-3 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000502:physiology*; D016133:Polymerase Chain Reaction; D060888:Real-Time Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D001618:beta-Lactamases / Q000097:blood
chemical_list: D017931:DNA Primers; D007377:Interleukin-3; D050799:STAT5 Transcription Factor; D015675:Osteocalcin; D007334:Insulin-Like Growth Factor I; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; C055184:beta-lactamase TEM-3; D001618:beta-Lactamases