TIEG-null mice display an osteopenic gender-specific phenotype

Hawse, John R.; Iwaniec, Urszula T.; Bensamoun, Sabine F.; Monroe, David G.; Peters, K.D.; Ilharreborde, Brice; Rajamannan, Nalini M.; Oursler, Merry Jo; Turner, Russell T.; Spelsberg, Thomas C.; Subramaniam, Malayannan

doi:10.1016/j.bone.2008.02.004

Cited by 50 publications

(56 citation statements)

References 37 publications

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“…Fixed femur from Rgs12 mutant and Cre control mice (n = 4) were analyzed and 3D reconstitution was used to determine bone volume (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th) as described. 25,51,52 Histology and histomorphometric analyses. Mice femurs and tibias were excised, fixed for 24 h in 10% natural buffered formalin, and decalcified in 10% EDTA for 1-2 weeks at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss

et al. 2015

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Regulators of G protein signaling (Rgs) have pivotal roles in controlling various cellular processes, such as cell differentiation. How Rgs proteins regulate osteoclast (OC) differentiation, function and bone homeostasis is poorly understood. It was previously demonstrated that Rgs12, the largest protein in the Rgs family, is predominantly expressed in OCs and regulates OC differentiation in vitro. To further understand the role and mechanism of Rgs12 in OC differentiation and bone diseases in vivo, we created OC-targeted Rgs12 knockout mice by using inducible Mx1-Cre and CD11b-Cre. Deletion of Rgs12 in hematopoietic cells or specifically in OC precursors resulted in increased bone mass with decreased OC numbers. Loss of Rgs12 impaired OC differentiation and function with impaired Ca 2+ oscillations and reduced nuclear factor of activated T cells (NFAT) 2 expression. The introduction of wild-type osteoblasts did not rescue the defective osteoclastogenesis. Ectopic expression of NFAT2 rescued defective OC differentiation in CD11b;Rgs12 fl/fl cells and promoted normal OC differentiation. Moreover, deletion of Rgs12 significantly inhibited pathological osteoclastogenesis and bone destruction in Rgs12-deficient mice that were subjected to ovariectomy and lipodysaccharide for bone loss. Thus our findings demonstrate that Rgs12 is an important regulator in OC differentiation and function and identify Rgs12 as a potential therapeutic target for osteoporosis and inflammation-induced bone loss. Bone homeostasis is tightly regulated by the balance between osteoblasts (OBs), the bone-forming cells, and osteoclasts (OCs), the bone-resorbing cells. 1 Pathological conditions such as osteoporosis, inflammation, and cancer break this balance in favor of the augmentation of OC activity, resulting in net bone loss. 2-4 As a result, patients with these diseases suffer from pain and risk of bone fracture. Therefore, understanding OC differentiation and function and uncovering potential therapeutic targets are very important and urgent objectives for treatment of these diseases. 5,6 Mature OCs, derived from the monocyte/macrophage hematopoietic lineage, are multinucleated and tartrateresistant acid phosphatase (TRAP) positive. 7 The breakthrough in understanding osteoclastogenesis came from the discovery that receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) have essential roles in stimulating monocyte-macrophage lineage cells to differentiate into mature and functional OCs. [8][9][10] Currently, known crucial RANKL downstream transcription factors and genes include active nuclear factor of activated T cells (NFAT) 2, c-Fos, β 3 -integrin, Cathepsin K, and matrix metallopeptidase 9. 11,12 Among these, NFAT2 acts as a master switch for the terminal differentiation of OCs. 13 Robust induction of NFAT2 is dependent on calcium (Ca 2+ ) oscillations. 14 Ca 2+ oscillations lead to calcineurin-mediated activation of NFAT2 and ensure NFAT2 long-lasting transcriptional activation. 13,14 Despite these...

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Section: Methodsmentioning

confidence: 99%

Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss

et al. 2015

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“…27 Additional studies have revealed microarchitecture changes in both cortical and trabecular bone in TIEG1 KO mice which is correlated with decreased bone strength and osteocytes density. 3,13 The purpose of the present study is to further elucidate the role of TIEG1 in osteocyte development as well as to characterize the morphological properties of osteocytes present in TIEG1 KO mouse bones.…”

Section: Introductionmentioning

confidence: 99%

Tieg1-Null Osteocytes Display Defects in Their Morphology, Density and Surrounding Bone Matrix

Haddad

Hawse

Subramaniam

et al. 2009

J. Musculoskelet. Res.

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Through the development of TGFβ-inducible early gene-1 (TIEG1) knockout (KO) mice, we have demonstrated that TIEG1 plays an important role in osteoblast-mediated bone mineralization, and in bone resistance to mechanical strain. To further investigate the influence of TIEG1 in skeletal maintenance, osteocytes were analyzed by transmission electron microscopy using TIEG1 KO and wild-type mouse femurs at one, three and eight months of age. The results revealed an age-dependent change in osteocyte surface and density, suggesting a role for TIEG1 in osteocyte development. Moreover, there was a decrease in the amount of hypomineralized bone matrix surrounding the osteocytes in TIEG1 KO mice relative to wild-type controls. While little is known about the function or importance of this hypomineralized bone matrix immediately adjacent to osteocytes, this study reveals significant differences in this bone microenvironment and suggests that osteocyte function may be compromised in the absence of TIEG1 expression.

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“…Detailed characterization of the intact skeleton has revealed that TIEG1 KO mice display a female specific osteopenic phenotype characterized by decreased bone mineral density and content, in both trabecular and cortical compartments, compared to wild-type (WT) littermates[11, 12]. Mechanical analysis of TIEG1 KO long bones using 3-point bending tests revealed significant decreases in their mechanical properties and strength relative to WT littermates[11, 12].…”

Section: Introductionmentioning

confidence: 99%

“…Mechanical analysis of TIEG1 KO long bones using 3-point bending tests revealed significant decreases in their mechanical properties and strength relative to WT littermates[11, 12]. Further investigation into the issue of the observed gender specific phenotype has demonstrated that TIEG1 expression is enhanced by estrogen[13] and is necessary to mediate maximal estrogen signaling throughout the mouse skeleton[14].…”

Section: Introductionmentioning

confidence: 99%

TIEG1 enhances Osterix expression and mediates its induction by TGFβ and BMP2 in osteoblasts

Subramaniam

Pitel

Withers

et al. 2016

Biochemical and Biophysical Research Communications

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Deletion of TIEG1/KLF10 in mice results in an osteopenic skeletal phenotype with significant decreases in both bone mineral density and content throughout the skeleton. Calvarial osteoblasts isolated from TIEG1 knockout (KO) mice display numerous changes in gene expression and exhibit significant delays in their mineralization rates relative to wild-type (WT) controls. Here, we demonstrate that loss of TIEG1 expression in osteoblasts results in decreased levels of Osterix mRNA. Suppression of TIEG1 expression in WT osteoblasts leads to decreased Osterix expression while restoration of TIEG1 expression in TIEG1 KO osteoblasts results in increased levels of Osterix. Transient transfection and chromatin immunoprecipitation assays reveal that TIEG1 directly binds to and activates the Osterix promoter and demonstrate that the zinc finger containing DNA binding domain of TIEG1 is necessary for this regulation. Furthermore, we reveal that TIEG1 expression is essential for the induction of Osterix expression by important bone-related cytokines such as TGFβ and BMP2 in osteoblast cells. Taken together, these data implicate an important role for TIEG1 in regulating the expression of Osterix, a master regulator of osteoblast differentiation and bone formation, and suggest that decreased expression of Osterix, as well as impaired TGFβ and BMP2 signaling, contribute to the observed osteopenic bone phenotype of TIEG1 KO mice.

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TIEG-null mice display an osteopenic gender-specific phenotype

Cited by 50 publications

References 37 publications

Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss

Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss

Tieg1-Null Osteocytes Display Defects in Their Morphology, Density and Surrounding Bone Matrix

TIEG1 enhances Osterix expression and mediates its induction by TGFβ and BMP2 in osteoblasts

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