title: Tob deficiency superenhances osteoblastic activity after ovariectomy to block estrogen deficiency-induced osteoporosis.
abstract: Tob (transducer of erbB2) is a member of antiproliferative family proteins and acts as a bone morphogenic protein inhibitor as well as a suppressor of proliferation in T cells, which have been implicated in postmenopausal bone loss. To determine the effect of Tob deficiency on estrogen deficiency-induced bone loss, we analyzed bone metabolism after ovariectomy or sham operation in Tob-deficient mice. Ovariectomy in WT mice decreased trabecular bone volume and bone mineral density (BMD) as expected. In Tob-deficient mice, ovariectomy reduced bone volume and BMD. However, even after ovariectomy, both trabecular bone volume and BMD levels in Tob-deficient bone were comparable to those in sham-operated WT bones. Bone formation parameters (mineral apposition rate and bone formation rate) in the ovariectomized Tob-deficient mice were significantly higher than those in the ovariectomized WT mice. In contrast, the ovariectomy-induced increase in the bone resorption parameters, osteoclast surface, and osteoclast number was similar between Tob-deficient mice and WT mice. Furthermore, in ex vivo nodule formation assay, ovariectomy-induced enhancement of nodule formation was significantly higher in the bone marrow cells from Tob-deficient mice than in the bone marrow cells from ovariectomized WT mice. Both Tob and estrogen signalings converge at bone morphogenic protein activation of alkaline phosphatase and GCCG-reporter gene expression in osteoblasts, revealing interaction between the two signals. These data indicate that Tob deficiency prevents ovariectomy-induced bone loss through the superenhancement of osteoblastic activities in bone and that this results in further augmentation in the bone formation rate and the mineral apposition rate after ovariectomy in vivo.
authors.affiliation: Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 3-10 Kanda-Surugadai 2-Chome, Chiyoda-Ku, Tokyo 101-0062, Japan.
authors.forename: Michihiko
authors.initials: M
authors.lastname: Usui
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Kunikazu
authors.initials: K
authors.lastname: Tsuji
authors.forename: Kaoru
authors.initials: K
authors.lastname: Oikawa
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
authors.forename: Isao
authors.initials: I
authors.lastname: Ishikawa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Nifuji
authors.forename: Masaki
authors.initials: M
authors.lastname: Noda
mesh_terms: D016475:3T3 Cells; D000469:Alkaline Phosphatase / Q000235:genetics; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D004967:Estrogens / Q000172:deficiency* / Q000502:physiology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000502:physiology*; D010024:Osteoporosis / Q000209:etiology / Q000517:prevention & control*; D010052:Ovariectomy; D010053:Ovary / Q000502:physiology* / Q000601:surgery; D015398:Signal Transduction / Q000502:physiology
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D004967:Estrogens; D047908:Intracellular Signaling Peptides and Proteins; C490903:Tob1 protein, mouse; D000469:Alkaline Phosphatase