scholarly journals The nucleocytoplasmic shuttling protein CIZ reduces adult bone mass by inhibiting bone morphogenetic protein–induced bone formation

2005 ◽  
Vol 201 (6) ◽  
pp. 961-970 ◽  
Author(s):  
Mikihiko Morinobu ◽  
Tetsuya Nakamoto ◽  
Kazunori Hino ◽  
Kunikazu Tsuji ◽  
Zhong-Jian Shen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Formation ◽  
Bone Mass ◽  
Mrna Expression ◽  
Bone Marrow Cells ◽  
Nucleocytoplasmic Shuttling ◽  
Morphogenetic Protein ◽  
Adult Bone ◽  
Deficient Mice

Osteoporosis is a major health problem; however, the mechanisms regulating adult bone mass are poorly understood. Cas-interacting zinc finger protein (CIZ) is a nucleocytoplasmic shuttling protein that localizes at cell adhesion plaques that form where osteoblasts attach to substrate. To investigate the potential role of CIZ in regulating adult bone mass, we examined the bones in CIZ-deficient mice. Bone volume was increased and the rates of bone formation were increased in CIZ-deficient mice, whereas bone resorption was not altered. CIZ deficiency enhanced the levels of mRNA expression of genes encoding proteins related to osteoblastic phenotypes, such as alkaline phosphatase (ALP) as well as osterix mRNA expression in whole long bones. Bone marrow cells obtained from the femora of CIZ-deficient mice revealed higher ALP activity in culture and formed more mineralized nodules than wild-type cells. CIZ deficiency enhanced bone morphogenetic protein (BMP)–induced osteoblastic differentiation in bone marrow cells in cultures, indicating that BMP is the target of CIZ action. CIZ deficiency increased newly formed bone mass after femoral bone marrow ablation in vivo. Finally, BMP-2–induced bone formation on adult mouse calvariae in vivo was enhanced by CIZ deficiency. These results establish that CIZ suppresses the levels of adult bone mass through inhibition of BMP-induced activation of osteoblasts.

scholarly journals A comparative study of the effects of genistein, estradiol and raloxifene on the murine skeletal system.

2009 ◽  
Vol 56 (2) ◽  
Author(s):  
Leszek Sliwiński ◽  
Joanna Folwarczna ◽  
Barbara Nowińska ◽  
Urszula Cegieła ◽  
Maria Pytlik ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Bone Marrow ◽  
Mrna Expression ◽  
Bone Marrow Cells ◽  
Bone Mineralization ◽  
Mouse Bone Marrow ◽  
Skeletal System ◽  
Mouse Bone Marrow Cells

Genistein, a major phytoestrogen of soy, is considered a potential drug for prevention and treatment of postmenopausal osteoporosis. The aim of the present study was to compare the effects of genistein, estradiol and raloxifene on the skeletal system in vivo and in vitro. Genistein (5 mg/kg), estradiol (0.1 mg/kg) or raloxifene hydrochloride (5 mg/kg) were administered daily by a stomach tube to mature ovariectomized Wistar rats for 4 weeks. Bone mass, mineral and calcium content, macrometric parameters and mechanical properties were examined. Also the effects of genistein, estradiol and raloxifene (10(-9)-10(-7) M) on the formation of osteoclasts from neonatal mouse bone marrow cells and the activity of osteoblasts isolated from neonatal mouse calvariae were compared. In vivo, estrogen deficiency resulted in the impairment of bone mineralization and bone mechanical properties. Raloxifene but not estradiol or genistein improved bone mineralization. Estradiol fully normalized the bone mechanical properties, whereas genistein augmented the deleterious effect of estrogen-deficiency on bone strength. In vitro, genistein, estradiol and raloxifene inhibited osteoclast formation from mouse bone marrow cells, decreasing the ratio of RANKL mRNA to osteoprotegerin mRNA expression in osteoblasts. Genistein, but not estradiol or raloxifene, decreased the ratio of alkaline phosphatase mRNA to ectonucleotide pyrophosphatase phosphodiesterase 1 mRNA expression in osteoblasts. This difference may explain the lack of genistein effect on bone mineralization observed in ovariectomized rats in the in vivo study. Concluding, our experiments demonstrated profound differences between the activities of genistein, estradiol and raloxifene towards the osseous tissue in experimental conditions.

STIMULATION OF BONE MARROW CELLS AND BONE FORMATION BY NACRE. IN VIVO AND IN VITRO STUDIES

Bioceramics ◽  
1999 ◽  
Author(s):  
M. Lamghari ◽  
S. Berland ◽  
A. Laurent ◽  
H. Huet ◽  
M.J. Almeida ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Formation ◽  
Bone Marrow Cells ◽  
In Vitro Studies ◽  
Stimulation Of ◽  
Marrow Cells

scholarly journals Integrin alpha11 is an Osteolectin receptor and is required for the maintenance of adult skeletal bone mass

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Bo Shen ◽  
Kristy Vardy ◽  
Payton Hughes ◽  
Alpaslan Tasdogan ◽  
Zhiyu Zhao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Mass ◽  
Bone Marrow Stromal Cells ◽  
Wnt Pathway ◽  
Leptin Receptor ◽  
Pathway Activation ◽  
Osteogenic Response ◽  
Skeletal Bone ◽  
Adult Bone ◽  
Deficient Mice

We previously discovered a new osteogenic growth factor that is required to maintain adult skeletal bone mass, Osteolectin/Clec11a. Osteolectin acts on Leptin Receptor+ (LepR+) skeletal stem cells and other osteogenic progenitors in bone marrow to promote their differentiation into osteoblasts. Here we identify a receptor for Osteolectin, integrin α11, which is expressed by LepR+ cells and osteoblasts. α11β1 integrin binds Osteolectin with nanomolar affinity and is required for the osteogenic response to Osteolectin. Deletion of Itga11 (which encodes α11) from mouse and human bone marrow stromal cells impaired osteogenic differentiation and blocked their response to Osteolectin. Like Osteolectin deficient mice, Lepr-cre; Itga11fl/fl mice appeared grossly normal but exhibited reduced osteogenesis and accelerated bone loss during adulthood. Osteolectin binding to α11β1 promoted Wnt pathway activation, which was necessary for the osteogenic response to Osteolectin. This reveals a new mechanism for maintenance of adult bone mass: Wnt pathway activation by Osteolectin/α11β1 signaling.

In vivo bone formation by human bone marrow cells: effect of osteogenic culture supplements and cell densities

1998 ◽  
Vol 9 (12) ◽  
pp. 855-858 ◽  
Author(s):  
S. C. MENDES ◽  
I. VAN DEN BRINK ◽  
J. D. DE BRUIJN ◽  
C. A. VAN BLITTERSWIJK
Keyword(s):  
Bone Marrow ◽  
Bone Formation ◽  
Bone Marrow Cells ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Cell Densities ◽  
In Vivo Bone Formation ◽  
Marrow Cells

scholarly journals BMP3 Suppresses Osteoblast Differentiation of Bone Marrow Stromal Cells via Interaction with Acvr2b

2012 ◽  
Vol 26 (1) ◽  
pp. 87-94 ◽  
Author(s):  
Shoichiro Kokabu ◽  
Laura Gamer ◽  
Karen Cox ◽  
Jonathan Lowery ◽  
Kunikazu Tsuji ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Formation ◽  
Bone Mass ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Physiological Role ◽  
Bmp Signaling ◽  
Marrow Stromal Cells ◽  
Colony Forming Unit ◽  
Adult Bone

Abstract Enhancing bone morphogenetic protein (BMP) signaling increases bone formation in a variety of settings that target bone repair. However, the role of BMP in the maintenance of adult bone mass is not well understood. Targeted disruption of BMP3 in mice results in increased trabecular bone formation, whereas transgenic overexpression of BMP3 in skeletal cells leads to spontaneous fracture, consistent with BMP3 having a negative role in bone mass regulation. Here we investigate the importance of BMP3 as a mediator of BMP signaling in the adult skeleton. We find that osteoblasts (OBL) and osteocytes are the source of BMP3 in adult bone. Using in vitro cultures of primary bone marrow stromal cells, we show that overexpression of BMP3 suppresses OBL differentiation, whereas loss of BMP3 increases colony-forming unit fibroblasts and colony-forming unit OBL. The ability of BMP3 to affect OBL differentiation is due to its interaction with activin receptor type 2b (Acvr2b) because knockdown of endogenous Acvr2b in bone marrow stromal cells reduces the suppressive effect of BMP3 on OBL differentiation. These findings best fit a model in which BMP3, produced by mature bone cells, acts to reduce BMP signaling through Acvr2b in skeletal progenitor cells, limiting their differentiation to mature OBL. Our data further support the idea that endogenous BMPs have a physiological role in regulating adult bone mass.

scholarly journals Integrin alpha11 is an Osteolectin receptor and is required for the maintenance of adult skeletal bone mass

2018 ◽  
Author(s):  
Bo Shen ◽  
Kristy Vardy ◽  
Payton Hughes ◽  
Alpaslan Tasdogan ◽  
Zhiyu Zhao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Mass ◽  
Bone Marrow Stromal Cells ◽  
Wnt Pathway ◽  
Leptin Receptor ◽  
Pathway Activation ◽  
Osteogenic Response ◽  
Skeletal Bone ◽  
Adult Bone ◽  
Deficient Mice

AbstractWe previously discovered a new osteogenic growth factor that is required to maintain adult skeletal bone mass, Osteolectin/Clec11a. Osteolectin acts on Leptin Receptor+(LepR+) skeletal stem cells and other osteogenic progenitors in bone marrow to promote their differentiation into osteoblasts. Here we identity a receptor for Osteolectin, α11 integrin, which is expressed by LepR+cells and osteoblasts. α11β1 integrin binds Osteolectin with nanomolar affinity and is required for the osteogenic response to Osteolectin. Deletion ofItga11(which encodes α11) from mouse and human bone marrow stromal cells impaired osteogenic differentiation and blocked their response to Osteolectin. LikeOsteolectindeficient mice,Lepr-cre;Itga11fl/flmice appeared grossly normal but exhibited reduced osteogenesis and accelerated bone loss during aging. Osteolectin binding to α11β1 promoted Wnt pathway activation, which was necessary for the osteogenic response to Osteolectin. This reveals a new mechanism for maintenance of adult bone mass: Wnt pathway activation by Osteolectin/α11β1 signaling.

VEGF and AMD3100-Induced Rapid Mobilization of C-Kit/Sca-1 Positive Murine Bone Marrow Cells and of Gr-1+/CD-11b+ Myeloid Cells Is Impaired in Urokinase (uPA) and Urokinase Receptor (uPAR) Deficient Mice.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1384-1384
Author(s):  
Mohammad Dehghani ◽  
Damla Olcaydu ◽  
Pavel Uhrin ◽  
Bernd Binder ◽  
Johannes Breuss
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Ex Vivo ◽  
Myeloid Cells ◽  
Urokinase Receptor ◽  
Facs Analysis ◽  
Β1 Integrins ◽  
Deficient Mice ◽  
Marrow Cells

Abstract Hematopoietic Progenitor Cells (HPC) can be mobilized from bone marrow into the circulation in response to a number of stimuli including G-CSF, AMD3100 (antagonist of CXCR4-DSF-1 axis) and vascular endothelial growth factor (VEGF). The main mechanism for mobilization of HPCs upon stimulation by classical “mobilizers”as G-CSF is thought to be through extracellular matrix proteolysis in the marrow. Urokinase is a serine protease present in the marrow and contributes to mobilization of stem cells upon binding to its receptor (uPAR) and activating plasminogen that leads to matrix degradation. Our previous data show that the effect of VEGF on endothelial cell migration is exerted through activation of the uPA/uPAR system and through co-internalization of β 1 integrins. Upon internalization of these receptors, cells detach from their underlying extra-cellular matrix (ECM) as well as from stromal cells. We hypothesize that the contribution of VEGF to HPC mobilization occurs through a similar mechanism. We also want to analyze the influence of uPA/uPAR deficiencies on mobilization of Gr-1+/CD-11b+ myeloid and c-kit +/Sca-1+ (SK)cells by VEGF and AMD3100 and compare it with G-CSF as a classical “mobilizer”. Wild type, uPA knockout and uPAR knockout mice in C57BL6 background were used for in vivo experiments. We collected peripheral blood before and 2 hours after i.p. injection of VEGF-E and AMD3100 and assessed the number of SK cells and myeloid cells by FACS analysis. We also administered G-CSF for 5 days and compared blood samples before and after the experiment. To evaluate the effect of VEGF on HPC integrin expression, femurs of the respective animals were incubated with VEGF in an ex vivo experimental model and β1 expression was assessed by FACS analysis. In vivo data demonstrated a significantly reduced responsiveness of uPA−/− mice to VEGF-E in the first 2 hours after the injection. This decreased responsiveness to VEGFis observed in uPAR−/− mice but to a lesser degree than in uPA−/− mice..(40 +/−16 % and21 +/− 20% respectively vs 65 +/− 24 % in wt, means and SD). Injection of urokinase together with VEGF to uPA−/− mice rescues the lack of mobilization of SK cells. Ex vivo stimulation of uPAR knockout femoral bone marrow cells with VEGF for 20 minutes provides evidence that the internalization of β1 integrins upon VEGF stimulation is uPAR dependent. VEGF can also increase in vivo the number of Gr-1+/CD-11b+ myeloid cells after 2 hours in wt mice (96 +/− 45%) but not in urokinase deficient or urokinase receptor deficient mice (7 +/− 11% and 21+/−33%, respectively). AMD3100 has a strong effect on mobilization of SK cells in wt animals within 2 hours (increase of 2.8+/−0.78 times) but cannot mobilize these cells in uPA and uPAR deficient mice to the same extend (0.8+/−0.65 times and 0.1+/−0.07 respectively). G-CSF injection for 5 days mobilizes Gr-1+/CD-11b+and SK cells in wt and knock out mice to a similar extent, indicating that the capacity to release these cells from the bone marrow is not affected by uPA or uPAR gene deficiency. Our results demonstrate a reduced mobilization of uPA−/− and uPAR−/− HPCs and myeloid cells in response to VEGF compared to wt mice. VEGF leads to internalization of the expression of β1 integrins on the surface of SK cells in wt but not in uPAR−/− mice. In addition, we could show that the uPA/uPAR system plays a role in AMD3100-dependent mobilization of these cells. These data indicate that the uPA – uPAR system plays a pivotal role in short-term but not long-term bone marrow HPC and PMN leukocyte mobilization.

Normal Neutrophil Function in Cathepsin G-Deficient Mice

Blood ◽  
1999 ◽  
Vol 94 (12) ◽  
pp. 4282-4293 ◽  
Author(s):  
Debra M. MacIvor ◽  
Steven D. Shapiro ◽  
Christine T.N. Pham ◽  
Abderazzaq Belaaouaj ◽  
Soman N. Abraham ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Neutrophil Function ◽  
Cathepsin G ◽  
Loss Of Function ◽  
Normal Morphology ◽  
Azurophil Granule ◽  
Myeloid Development ◽  
Deficient Mice

Cathepsin G is a neutral serine protease that is highly expressed at the promyelocyte stage of myeloid development. We have developed a homologous recombination strategy to create a loss-of-function mutation for murine cathepsin G. Bone marrow derived from mice homozygous for this mutation had no detectable cathepsin G protein or activity, indicating that no other protease in bone marrow cells has the same specificity. Hematopoiesis in cathepsin G−/− mice is normal, and the mice have no overt abnormalities in blood clotting. Neutrophils derived from cathepsin G−/− mice have normal morphology and azurophil granule composition; these neutrophils also display normal phagocytosis and superoxide production and have normal chemotactic responses to C5a, fMLP, and interleukin-8. Although cathepsin G has previously shown to have broad spectrum antibiotic properties, challenges of mice with Staphylococcus aureus, Klebsiella pneumoniae, or Escherichia coli yielded survivals that were not different from those of wild-type animals. In sum, cathepsin G−/− neutrophils have no obvious defects in function; either cathepsin G is not required for any of these normal neutrophil functions or related azurophil granule proteases with different specificities (ie, neutrophil elastase, proteinase 3, azurocidin, and/or others) can substitute for it in vivo.

Sign in / Sign up

Export Citation Format

Share Document