title: Sympathetic control of bone mass regulated by osteopontin.
abstract: The sympathetic nervous system suppresses bone mass by mechanisms that remain incompletely elucidated. Using cell-based and murine genetics approaches, we show that this activity of the sympathetic nervous system requires osteopontin (OPN), a cytokine and one of the major members of the noncollagenous extracellular matrix proteins of bone. In this work, we found that the stimulation of the sympathetic tone by isoproterenol increased the level of OPN expression in the plasma and bone and that mice lacking OPN (OPN-KO) suppressed the isoproterenol-induced bone loss by preventing reduced osteoblastic and enhanced osteoclastic activities. In addition, we found that OPN is necessary for changes in the expression of genes related to bone resorption and bone formation that are induced by activation of the sympathetic tone. At the cellular level, we showed that intracellular OPN modulated the capacity of the β2-adrenergic receptor to generate cAMP with a corresponding modulation of cAMP-response element binding (CREB) phosphorylation and associated transcriptional events inside the cell. Our results indicate that OPN plays a critical role in sympathetic tone regulation of bone mass and that this OPN regulation is taking place through modulation of the β2-adrenergic receptor/cAMP signaling system.
authors: Department of Molecular Pharmacology, Medical Research Institute, and Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases,  Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, 113-8510 Tokyo,  Japan.
authors: Masashi
authors: M
authors: Nagao
authors: Timothy N
authors: TN
authors: Feinstein
authors: Yoichi
authors: Y
authors: Ezura
authors: Tadayoshi
authors: T
authors: Hayata
authors: Takuya
authors: T
authors: Notomi
authors: Yoshitomo
authors: Y
authors: Saita
authors: Ryo
authors: R
authors: Hanyu
authors: Hiroaki
authors: H
authors: Hemmi
authors: Yayoi
authors: Y
authors: Izu
authors: Shu
authors: S
authors: Takeda
authors: Kathryn
authors: K
authors: Wang
authors: Susan
authors: S
authors: Rittling
authors: Tetsuya
authors: T
authors: Nakamoto
authors: Kazuo
authors: K
authors: Kaneko
authors: Hisashi
authors: H
authors: Kurosawa
authors: Gerard
authors: G
authors: Karsenty
authors: David T
authors: DT
authors: Denhardt
authors: Jean-Pierre
authors: JP
authors: Vilardaga
authors: Masaki
authors: M
authors: Noda
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D053495:Osteopontin / Q000172:deficiency / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*
chemical_list: D018343:Receptors, Adrenergic, beta-2; C506896:Spp1 protein, mouse; D053495:Osteopontin; D000242:Cyclic AMP; D007545:Isoproterenol