scholarly journals p53 functions as a negative regulator of osteoblastogenesis, osteoblast-dependent osteoclastogenesis, and bone remodeling

2005 ◽  
Vol 172 (1) ◽  
pp. 115-125 ◽  
Author(s):  
Xueying Wang ◽  
Hui-Yi Kua ◽  
Yuanyu Hu ◽  
Ke Guo ◽  
Qi Zeng ◽  
...  
Keyword(s):  
Bone Remodeling ◽  
Osteoblast Differentiation ◽  
Osteoclast Differentiation ◽  
Negative Regulator ◽  
High Bone Mass ◽  
Independent Manner ◽  
Interacting Protein ◽  
High Bone ◽  
Macrophage Colony ◽  
High Bone Mass Phenotype

p53 is a well known tumor suppressor. We show that p53 also regulates osteoblast differentiation, bone formation, and osteoblast-dependent osteoclast differentiation. Indeed, p53−/− mice display a high bone mass phenotype, and p53−/− osteoblasts show accelerated differentiation, secondary to an increase in expression of the osteoblast differentiation factor osterix, as a result. Reporter assays indicate that p53 represses osterix transcription by the minimal promoter in a DNA-binding–independent manner. In addition, p53−/− osteoblasts have an enhanced ability to favor osteoclast differentiation, in association with an increase in expression of macrophage-colony stimulating factor, which is under the control of osterix. Furthermore, inactivating p53 is sufficient to rescue the osteoblast differentiation defects observed in mice lacking c-Abl, a p53-interacting protein. Thus, these results identify p53 as a novel regulator of osteoblast differentiation, osteoblast-dependent osteoclastogenesis, and bone remodeling.

scholarly journals Cart Overexpression Is the Only Identifiable Cause of High Bone Mass in Melanocortin 4 Receptor Deficiency

Endocrinology ◽  
2006 ◽  
Vol 147 (7) ◽  
pp. 3196-3202 ◽  
Author(s):  
Jong Deok Ahn ◽  
Beatrice Dubern ◽  
Cecile Lubrano-Berthelier ◽  
Karine Clement ◽  
Gerard Karsenty
Keyword(s):  
Energy Metabolism ◽  
Bone Resorption ◽  
Bone Mass ◽  
Bone Remodeling ◽  
Neural Control ◽  
Osteoclast Differentiation ◽  
Serum Levels ◽  
High Bone Mass ◽  
Melanocortin 4 Receptor ◽  
High Bone

The neural regulation of bone remodeling has proven to be increasingly complex at the molecular level because it involves both positive and negative mediators of bone formation and resorption. One of the mediators expressed in hypothalamic neurons that leptin uses to inhibit osteoclast differentiation and thereby bone resorption is cocaine- and amphetamine-regulated transcript (CART). CART expression in the hypothalamus is increased in mice lacking melanocortin 4 receptor (Mc4r−/− mice). Moreover, we show here that humans or mice lacking only one allele of Mc4r display a decrease in bone resorption parameters, high bone mass, and an increase in CART serum levels and/or hypothalamic expression. To demonstrate that the Cart overexpression is the only identifiable cause for the high bone mass observed upon Mc4r inactivation, we removed one allele of Cart from mice either heterozygous or homozygous for Mc4r inactivation. This manipulation sufficed to either significantly improve or normalize bone resorption parameters, without improving the energy metabolism disturbance that characterizes Mc4r-deficient mice. These results identify CART signaling as the main if not only molecular pathway accounting for the decrease in bone resorption leading to high bone mass in mice and humans deficient in Mc4r. As importantly, they also indicate that CART regulates bone resorption independently of the role it may exert in energy metabolism, suggesting that the neural control of appetite and bone remodeling are independent of each other.

scholarly journals In Vivo Analysis of Wnt Signaling in Bone

Endocrinology ◽  
2007 ◽  
Vol 148 (6) ◽  
pp. 2630-2634 ◽  
Author(s):  
Donald A. Glass ◽  
Gerard Karsenty
Keyword(s):  
Bone Mass ◽  
Wnt Signaling ◽  
Bone Remodeling ◽  
Signaling Pathway ◽  
Mouse Models ◽  
Osteoclast Differentiation ◽  
Wnt Signaling Pathway ◽  
Human Beings ◽  
High Bone Mass ◽  
High Bone

Bone remodeling requires osteoblasts and osteoclasts working in concert to maintain a constant bone mass. The dysregulation of signaling pathways that affect osteoblast or osteoclast differentiation or function leads to either osteopenia or high bone mass. The discovery that activating and inactivating mutations in low-density lipoprotein receptor-related protein 5, a putative Wnt coreceptor, led to high bone mass and low bone mass in human beings, respectively, generated a tremendous amount of interest in the possible role of the Wnt signaling pathway in the regulation of bone remodeling. A number of mouse models have been generated to study a collection of Wnt signaling molecules that have been identified as regulators of bone mass. These mouse models help establish the canonical Wnt signaling pathway as a major regulator of chondrogenesis, osteoblastogenesis, and osteoclastogenesis. This review will summarize these advances.

scholarly journals Maf1, a repressor of RNA polymerase III-dependent transcription, regulates bone mass

2021 ◽  
Author(s):  
Ellen Busschers ◽  
Naseer Ahmad ◽  
Li Sun ◽  
James R Iben ◽  
Christopher J. Walkey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Mass ◽  
Rna Polymerase ◽  
Osteoblast Differentiation ◽  
Rna Polymerase Iii ◽  
High Bone Mass ◽  
Polymerase Iii ◽  
High Bone ◽  
High Bone Mass Phenotype ◽  
Pol Iii

Maf1, a key repressor of RNA polymerase III-mediated transcription, has been shown to promote mesoderm formation in vitro. Here, we show for the first time that Maf1 plays a critical role in the regulation of osteoblast differentiation and bone mass. A high bone mass phenotype was noted in mice with global deletion of Maf1 (Maf1-/- mice), as well as paradoxically, in mice that overexpressed MAF1 in cells of the osteoblast lineage (Prx-Cre;LSL-Maf1 mice). Osteoblasts isolated from Maf1-/- mice unexpectedly showed reduced osteoblastogenesis ex vivo. Prx-Cre;LSL-Maf1 mice showed enhanced osteoblastogenesis concordant with their high bone mass phenotype. Thus, the high bone mass phenotype in Maf1-/- mice is likely due to the confounding effects of the global absence of MAF1 in Maf1-/- mice. Expectedly, MAF1 overexpression promoted osteoblast differentiation and shRNA-mediated Maf1 downregulation inhibited differentiation of ST2 cells, indicating an overall positive action of Maf1 on osteoblast formation. We also found that, in contrast to MAF1 overexpression, other perturbations that repress RNA pol III transcription, including Brf1 knockdown and the chemical inhibition of RNA pol III by ML-60218, paradoxically inhibited osteoblast differentiation. RNA-seq was used to determine the basis for these opposing actions. The three modalities used to perturb RNA pol III transcription resulted in distinct changes gene expression, indicating that this transcription process is highly sensitive and triggers diverse gene expression programs and phenotypic outcomes. Specifically, MAF1 overexpression in ST2 cells induced genes known to promote osteoblast differentiation. A subset of these genes was altered in an opposite manner with Brf1 downregulation or treatment with ML-60218, both of which also inhibit RNA pol III-mediated transcription. All these perturbations, however, enhanced adipogenesis in ST2 cell cultures. Furthermore, codon bias was observed in a subset of genes expressed during osteoblast differentiation. Together, these results reveal a novel role for Maf1 and RNA pol III-mediated transcription in osteoblast fate determination and differentiation and bone mass regulation.

scholarly journals Monosodium Glutamate-Sensitive Hypothalamic Neurons Contribute to the Control of Bone Mass

Endocrinology ◽  
2003 ◽  
Vol 144 (9) ◽  
pp. 3842-3847 ◽  
Author(s):  
Florent Elefteriou ◽  
Shu Takeda ◽  
Xiuyun Liu ◽  
Dawna Armstrong ◽  
Gerard Karsenty
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Mass ◽  
Monosodium Glutamate ◽  
Hypothalamic Neurons ◽  
High Bone Mass ◽  
Independent Manner ◽  
Normal Bone ◽  
High Bone ◽  
High Bone Mass Phenotype

Abstract Using chemical lesioning we previously identified hypothalamic neurons that are required for leptin antiosteogenic function. In the course of these studies we observed that destruction of neurons sensitive to monosodium glutamate (MSG) in arcuate nuclei did not affect bone mass. However MSG treatment leads to hypogonadism, a condition inducing bone loss. Therefore the normal bone mass of MSG-treated mice suggested that MSG-sensitive neurons may be implicated in the control of bone mass. To test this hypothesis we assessed bone resorption and bone formation parameters in MSG-treated mice. We show here that MSG-treated mice display the expected increase in bone resorption and that their normal bone mass is due to a concomitant increase in bone formation. Correction of MSG-induced hypogonadism by physiological doses of estradiol corrected the abnormal bone resorptive activity in MSG-treated mice and uncovered their high bone mass phenotype. Because neuropeptide Y (NPY) is highly expressed in MSG-sensitive neurons we tested whether NPY regulates bone formation. Surprisingly, NPY-deficient mice had a normal bone mass. This study reveals that distinct populations of hypothalamic neurons are involved in the control of bone mass and demonstrates that MSG-sensitive neurons control bone formation in a leptin-independent manner. It also indicates that NPY deficiency does not affect bone mass.

scholarly journals Sex dimorphic regulation of osteoprogenitor progesterone in bone stromal cells

2017 ◽  
Vol 59 (4) ◽  
pp. 351-363 ◽  
Author(s):  
Alexander Kot ◽  
Zhendong A Zhong ◽  
Hongliang Zhang ◽  
Yu-An Evan Lay ◽  
Nancy E Lane ◽  
...  
Keyword(s):  
Mouse Model ◽  
Bone Mass ◽  
Gene Transcription ◽  
Conditional Knockout ◽  
Sequencing Analysis ◽  
Wild Type ◽  
High Bone Mass ◽  
Matrix Interaction ◽  
High Bone ◽  
High Bone Mass Phenotype

Increasing peak bone mass is a promising strategy to prevent osteoporosis. A mouse model of global progesterone receptor (PR) ablation showed increased bone mass through a sex-dependent mechanism. Cre-Lox recombination was used to generate a mouse model of osteoprogenitor-specific PR inactivation, which recapitulated the high bone mass phenotype seen in the PR global knockout mouse mode. In this work, we employed RNA sequencing analysis to evaluate sex-independent and sex-dependent differences in gene transcription of osteoprogenitors of wild-type and PR conditional knockout mice. PR deletion caused marked sex hormone-dependent changes in gene transcription in male mice as compared to wild-type controls. These transcriptional differences revealed dysregulation in pathways involving immunomodulation, osteoclasts, bone anabolism, extracellular matrix interaction and matrix interaction. These results identified many potential mechanisms that may explain our observed high bone mass phenotype with sex differences when PR was selectively deleted in the MSCs.

scholarly journals Novel LRP5 Missense Mutation in a Patient With a High Bone Mass Phenotype Results in Decreased DKK1-Mediated Inhibition of Wnt Signaling*

2007 ◽  
Vol 22 (5) ◽  
pp. 708-716 ◽  
Author(s):  
Wendy Balemans ◽  
Jean-Pierre Devogelaer ◽  
Erna Cleiren ◽  
Elke Piters ◽  
Emanuelle Caussin ◽  
...  
Keyword(s):  
Bone Mass ◽  
Wnt Signaling ◽  
Missense Mutation ◽  
High Bone Mass ◽  
High Bone ◽  
High Bone Mass Phenotype
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