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 Tobdeficient 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 ovariectomyinduced 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.

ANA Deficiency Enhances Bone Morphogenetic Protein-induced Ectopic Bone Formation via Transcriptional Events

“…For instance, deletion of Noggin deteriorates embryonic joint development severely and results in embryonic lethality (28). Deficiency of Tob and Caf1 is not lethal but enhances bone volume in the cancellous bone envelope in adult mice (15,21,29). In contrast, ANA deficiency specifically suppresses the level of BMP-induced ectopic bone formation, but it does not affect the levels of bone mass systemically, post-injury recovery of bone formation, or morphology of the joints and skeleton.…”

“…Among the members of Tob/BTG family, Tob was shown to be a BMP antagonist previously (14,15). However, effects of other members of Tob/BTG family on BMP activity have not yet been fully understood.…”

Investigation of central versus peripheral effects of estradiol in ovariectomized mice

“…The present study provides important information regarding the dose-response of estrogen on several estrogen-responsive tissues, including the uterus, the thymus, the retroperitoneal fat depot as well as the cortical and the trabecular bone compartments separately. Furthermore, due to the development of a large number of genetically engineered mouse models, the ovariectomized mouse model has been frequently used as an animal model for postmenopausal osteoporosis (Lindberg et al 2002, Hikiji et al 2004, Usui et al 2004. It is therefore surprising that very few studies have characterized the dose-response effect of E2 in different tissues in this model (Mödder et al 2004).…”

Current Topics in Pharmacological Research on Bone Metabolism: Regulation of Bone Mass by the Function of Endogenous Modulators of Bone Morphogenetic Protein in Adult Stage

“…To do this, we chose a mouse system where ovariectomy was conducted to simulate bone turnover in post menopausal women. In wild type mice subjected to ovariectomy, reduced trabecular bone mass was observed previously (4). In Tob knockout mice, basal bone mass is significantly higher than bone mass levels in wild type and sham control mice.…”