scholarly journals Genome-wide screening in human growth plates during puberty in one patient suggests a role for RUNX2 in epiphyseal maturation

2011 ◽  
Vol 209 (2) ◽  
pp. 245-254 ◽  
Author(s):  
Joyce Emons ◽  
Bas E Dutilh ◽  
Eva Decker ◽  
Heide Pirzer ◽  
Carsten Sticht ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Growth Plate ◽  
Bone Growth ◽  
Target Genes ◽  
Morphological Changes ◽  
Human Growth ◽  
Tanner Stage ◽  
Plate Height ◽  
Promoter Regions ◽  
Evolutionarily Conserved

In late puberty, estrogen decelerates bone growth by stimulating growth plate maturation. In this study, we analyzed the mechanism of estrogen action using two pubertal growth plate specimens of one girl at Tanner stage B2 and Tanner stage B3. Histological analysis showed that progression of puberty coincided with characteristic morphological changes: a decrease in total growth plate height (P=0.002), height of the individual zones (P<0.001), and an increase in intercolumnar space (P<0.001). Microarray analysis of the specimens identified 394 genes (72% upregulated and 28% downregulated) that changed with the progression of puberty. Overall changes in gene expression were small (average 1.38-fold upregulated and 1.36-fold downregulated genes). The 394 genes mapped to 13 significantly changing pathways (P<0.05) associated with growth plate maturation (e.g. extracellular matrix, cell cycle, and cell death). We next scanned the upstream promoter regions of the 394 genes for the presence of evolutionarily conserved binding sites for transcription factors implicated in growth plate maturation such as estrogen receptor (ER), androgen receptor, ELK1, STAT5B, cyclic AMP response element (CREB), and RUNX2. High-quality motif sites for RUNX2 (87 genes), ELK1 (43 genes), and STAT5B (31 genes), but not ER, were evolutionarily conserved, indicating their functional relevance across primates. Moreover, we show that some of these sites are direct target genes of these transcription factors as shown by ChIP assays.

scholarly journals Mediator complex subunit Med19 binds directly GATA transcription factors and is required with Med1 for GATA-driven gene regulation in vivo

2020 ◽  
Vol 295 (39) ◽  
pp. 13617-13629
Author(s):  
Clément Immarigeon ◽  
Sandra Bernat-Fabre ◽  
Emmanuelle Guillou ◽  
Alexis Verger ◽  
Elodie Prince ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Direct Interaction ◽  
Mediator Complex ◽  
Loss Of Function ◽  
Transcriptional Responses ◽  
Rna Pol Ii ◽  
Evolutionarily Conserved

The evolutionarily conserved multiprotein Mediator complex (MED) serves as an interface between DNA-bound transcription factors (TFs) and the RNA Pol II machinery. It has been proposed that each TF interacts with a dedicated MED subunit to induce specific transcriptional responses. But are these binary partnerships sufficient to mediate TF functions? We have previously established that the Med1 Mediator subunit serves as a cofactor of GATA TFs in Drosophila, as shown in mammals. Here, we observe mutant phenotype similarities between another subunit, Med19, and the Drosophila GATA TF Pannier (Pnr), suggesting functional interaction. We further show that Med19 physically interacts with the Drosophila GATA TFs, Pnr and Serpent (Srp), in vivo and in vitro through their conserved C-zinc finger domains. Moreover, Med19 loss of function experiments in vivo or in cellulo indicate that it is required for Pnr- and Srp-dependent gene expression, suggesting general GATA cofactor functions. Interestingly, Med19 but not Med1 is critical for the regulation of all tested GATA target genes, implying shared or differential use of MED subunits by GATAs depending on the target gene. Lastly, we show a direct interaction between Med19 and Med1 by GST pulldown experiments indicating privileged contacts between these two subunits of the MED middle module. Together, these findings identify Med19/Med1 as a composite GATA TF interface and suggest that binary MED subunit–TF partnerships are probably oversimplified models. We propose several mechanisms to account for the transcriptional regulation of GATA-targeted genes.

scholarly journals RECENT RESEARCH ON THE GROWTH PLATE: Recent insights into the regulation of the growth plate

2014 ◽  
Vol 53 (1) ◽  
pp. T1-T9 ◽  
Author(s):  
Julian C Lui ◽  
Ola Nilsson ◽  
Jeffrey Baron
Keyword(s):  
Growth Plate ◽  
Bone Morphogenetic Proteins ◽  
Bone Growth ◽  
Association Studies ◽  
Expression Patterns ◽  
Human Growth ◽  
Cytokine Signaling ◽  
Genome Wide Association Studies ◽  
Paracrine Factors ◽  
Large Numbers

For most bones, elongation is driven primarily by chondrogenesis at the growth plates. This process results from chondrocyte proliferation, hypertrophy, and extracellular matrix secretion, and it is carefully orchestrated by complex networks of local paracrine factors and modulated by endocrine factors. We review here recent advances in the understanding of growth plate physiology. These advances include new approaches to study expression patterns of large numbers of genes in the growth plate, using microdissection followed by microarray. This approach has been combined with genome-wide association studies to provide insights into the regulation of the human growth plate. We also review recent studies elucidating the roles of bone morphogenetic proteins, fibroblast growth factors, C-type natriuretic peptide, and suppressor of cytokine signaling in the local regulation of growth plate chondrogenesis and longitudinal bone growth.

scholarly journals Bortezomib Is Cytotoxic to the Human Growth Plate and Permanently Impairs Bone Growth in Young Mice

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e50523 ◽  
Author(s):  
Emma Eriksson ◽  
Farasat Zaman ◽  
Dionisios Chrysis ◽  
Henrik Wehtje ◽  
Terhi J. Heino ◽  
...  
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Human Growth ◽  
Young Mice

Mechanics and Validation of an in Vivo Device to Apply Torsional Loading to Caudal Vertebrae

2013 ◽  
Vol 135 (8) ◽  
Author(s):  
Robert Rizza ◽  
XueCheng Liu
Keyword(s):  
Finite Element ◽  
Growth Plate ◽  
Morphological Changes ◽  
Histological Study ◽  
Torsional Loading ◽  
Plate Height ◽  
Torsional Load ◽  
Caudal Vertebrae ◽  
Applied Torque

Axial loading of vertebral bodies has been shown to modulate growth. Longitudinal growth of the vertebral body is impaired by compressive forces while growth is stimulated by distraction. Investigations of torsional loading on the growth plate in the literature are few. The purposes of this study were two-fold: (1) to develop a torque device to apply torsional loads on caudal vertebrae and (2) investigate numerically and in vivo the feasibility of the application of the torque on the growth plate. A controllable torque device was developed and validated in the laboratory. A finite element study was implemented to examine mechanically the deformation of the growth plate and disk. A rat tail model was used with six 5-week-old male Sprague-Dawley rats. Three rats received a static torsional load, and three rats received no torque and served as sham control rats. A histological study was undertaken to investigate possible morphological changes in the growth plate, disk, and caudal bone. The device successfully applied a controlled torsional load to the caudal vertebrae. The limited study using finite element analysis (FEA) and histology demonstrated that applied torque increased lateral disk height and increased disk width. The study also found that the growth plate height increased, and the width decreased as well as a curved displacement of the growth plate. No significant changes were observed from the in vivo study in the bone. The torsional device does apply controlled torque and is well tolerated by the animal. This study with limited samples appears to result in morphological changes in the growth plate and disk. The use of this device to further investigate changes in the disk and growth plate is feasible.

scholarly journals Co-operation between the PAI and RED subdomains of Pax-8 in the interaction with the thyroglobulin promoter

1999 ◽  
Vol 337 (2) ◽  
pp. 253-262 ◽  
Author(s):  
Lucia PELLIZZARI ◽  
Gianluca TELL ◽  
Giuseppe DAMANTE
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Dna Sequences ◽  
Target Genes ◽  
Dna Recognition ◽  
Cell Types ◽  
Full Length ◽  
Paired Domain ◽  
Binding Properties ◽  
Evolutionarily Conserved

Pax proteins are transcription factors that play an important role in the differentiation of several cell types. These proteins bind to specific DNA sequences through the paired domain. This evolutionarily conserved element is composed of two subdomains (PAI and RED), located at the N- and C-terminals, respectively. Due to the presence of these two subdomains, Pax proteins may recognize DNA in different modes, a possibility that has not been exhaustively explored yet. The C site of the thyroglobulin promoter is bound by the thyroid-specific transcription factor Pax-8. In this study we have characterized the mode by which the Pax-8 paired domain interacts with the C site. Results allow the identification of the respective positions of the PAI and RED subdomains when the full-length protein is bound to the C site. The binding of the isolated PAI and RED subdomains to the C site and to several related mutants was also evaluated. Both subdomains interact with DNA as a monomer and display a lower binding affinity than the full-length protein. Therefore, the Pax-8 paired domain–C site interaction occurs through a co-operation between the two subdomains. The binding properties of the PAI subdomain suggest that the co-operation between PAI and RED subdomains does not merely consist of the sum of contacts established by the single subdomain: the presence of the RED subdomain is necessary for correct DNA recognition by the PAI subdomain, thus accounting for a sort of chronology of events during DNA binding. Since the RED subdomain is much more variable than the PAI subdomain among Pax proteins, these results could explain how distinct Pax proteins may select different target genes.

scholarly journals The role of estrogen receptor-α and its activation function-1 for growth plate closure in female mice

2012 ◽  
Vol 302 (11) ◽  
pp. E1381-E1389 ◽  
Author(s):  
A. E. Börjesson ◽  
S. H. Windahl ◽  
E. Karimian ◽  
E. E. Eriksson ◽  
M. K. Lagerquist ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Growth Plate ◽  
Bone Growth ◽  
High Dose ◽  
Plate Height ◽  
Chondrocyte Proliferation ◽  
Growth Plates ◽  
Longitudinal Bone Growth ◽  
Female Mice

High estradiol levels in late puberty induce growth plate closure and thereby cessation of growth in humans. In mice, the growth plates do not fuse after sexual maturation, but old mice display reduced longitudinal bone growth and high-dose estradiol treatment induces growth plate closure. Estrogen receptor (ER)-α stimulates gene transcription via two activation functions (AFs), AF-1 and AF-2. To evaluate the role of ERα and its AF-1 for age-dependent reduction in longitudinal bone growth and growth plate closure, female mice with inactivation of ERα (ERα−/−) or ERαAF-1 (ERαAF-10) were evaluated. Old (16- to 19-mo-old) female ERα−/− mice showed continued substantial longitudinal bone growth, resulting in longer bones (tibia: +8.3%, P < 0.01) associated with increased growth plate height (+18%, P < 0.05) compared with wild-type (WT) mice. In contrast, the longitudinal bone growth ceased in old ERαAF-10 mice (tibia: −4.9%, P < 0.01). Importantly, the proximal tibial growth plates were closed in all old ERαAF-10 mice while they were open in all WT mice. Growth plate closure was associated with a significantly altered balance between chondrocyte proliferation and apoptosis in the growth plate. In conclusion, old female ERα−/− mice display a prolonged and enhanced longitudinal bone growth associated with increased growth plate height, resembling the growth phenotype of patients with inactivating mutations in ERα or aromatase. In contrast, ERαAF-1 deletion results in a hyperactive ERα, altering the chondrocyte proliferation/apoptosis balance, leading to growth plate closure. This suggests that growth plate closure is induced by functions of ERα that do not require AF-1 and that ERαAF-1 opposes growth plate closure.

scholarly journals A Mixture of Humulus japonicus Increases Longitudinal Bone Growth Rate in Sprague Dawley Rats

Nutrients ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2625
Author(s):  
Ok-Kyung Kim ◽  
Jeong moon Yun ◽  
Minhee Lee ◽  
Soo-Jeung Park ◽  
Dakyung Kim ◽  
...  
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Tail Length ◽  
Janus Kinase ◽  
Sprague Dawley ◽  
Plate Height ◽  
Longitudinal Bone Growth ◽  
Sd Rats ◽  
Humulus Japonicus ◽  
Igfbp 3

The aim of this study was to investigate the effects of administration of a mixture of Humulus japonicus (MH) on longitudinal bone growth in normal Sprague Dawley (SD) rats. We measured the femur and tibia length, growth plate area, proliferation of chondrocytes, and expression of insulin-like growth factor-1 (IGF-I) and IGF binding protein-3 (IGFBP-3), and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) phosphorylation after dietary administration of MH in SD rats for four weeks. The nose–tail length gain and length of femur and tibia increased significantly in the group that received MH for a period of four weeks. We performed H&E staining and Bromodeoxyuridine/5-Bromo-2′-Deoxyuridine (BrdU) staining to examine the effect of dietary administration of MH on the growth plate and the proliferation of chondrocytes and found that MH stimulated the proliferation of chondrocytes and contributed to increased growth plate height during the process of longitudinal bone growth. In addition, serum levels of IGF-1 and IGFBP-3 and expression of IGF-1 and IGFBP-3 mRNAs in the liver and bone were increased, and phosphorylation of JAK2/STAT5 in the liver was increased in the MH groups. Based on these results, we suggest that the effect of MH on longitudinal bone growth is mediated by increased JAK2/STAT5-induced IGF-1 production.

scholarly journals Regulation of bone growth via ligand-specific activation of estrogen receptor alpha

2017 ◽  
Vol 232 (3) ◽  
pp. 403-410 ◽  
Author(s):  
Maryam Iravani ◽  
Marie Lagerquist ◽  
Claes Ohlsson ◽  
Lars Sävendahl
Keyword(s):  
Estrogen Receptor ◽  
Side Effects ◽  
Growth Plate ◽  
Bone Growth ◽  
High Dose ◽  
Tall Stature ◽  
Plate Height ◽  
Estrogenic Effects ◽  
Increased Risk ◽  
Risk Of Cancer

Estrogens are well known for their capacity to promote bone maturation and at high doses to induce growth plate closure and thereby stop further growth. High-dose estrogen treatment has therefore been used to limit growth in extremely tall girls. However, recent data suggest that this treatment may have severe side effects, including increased risk of cancer and reduced fertility. We hypothesized that estrogenic effects in bone are mediated via ERα signaling. Twelve-week-old ovariectomized female C57BL/6 mice were subcutaneously injected for 4 weeks with E2 or selective ERα (PPT) or ERβ (DPN) agonists. After killing, tibia and femur lengths were measured, and growth plate morphology was analyzed. E2- and PPT-treated mice had shorter tibiae and femur bones when compared to vehicle-treated controls, whereas animals treated with DPN had similar bone lengths compared to controls. Growth plate height and hypertrophic zone height were reduced in animals treated with E2 or PPT but not in those treated with DPN, supporting that the effect was mediated via ERα. Moreover, PCNA staining revealed suppressed proliferation of chondrocytes in the tibia growth plate in PPT- or E2-treated mice compared to controls. Our data show that estrogenic effects on bone growth and growth plate maturation are mainly mediated via ERα. Our findings may have direct implications for the development of new and more selective treatment modalities of extreme tall stature using selective estrogen receptor modulators that may have low side effects than high-dose E2 treatment.

scholarly journals Radial shockwave treatment promotes chondrogenesis in human growth plate and longitudinal bone growth in rabbits

Bone ◽  
2022 ◽  
Vol 154 ◽  
pp. 116186
Author(s):  
Sowmya Ramesh ◽  
Farasat Zaman ◽  
Lars Sävendahl ◽  
Vrisha Madhuri
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Human Growth ◽  
Longitudinal Bone Growth

DNA methylation events in transcription factors and gene expression changes in colon cancer

Epigenomics ◽  
2020 ◽  
Vol 12 (18) ◽  
pp. 1593-1610
Author(s):  
Anna Díez-Villanueva ◽  
Rebeca Sanz-Pamplona ◽  
Robert Carreras-Torres ◽  
Ferran Moratalla-Navarro ◽  
M Henar Alonso ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Colon Cancer ◽  
Transcription Factors ◽  
Target Genes ◽  
Linear Models ◽  
Cpg Islands ◽  
Promoter Regions ◽  
Differential Gene

Aim: Gain insight about the role of DNA methylation in the malignant growth of colon cancer. Patients & methods: Methylation and gene expression from 90 adjacent-tumor paired tissues and 48 healthy tissues were analyzed. Tumor genes whose change in expression was explained by changes in methylation were identified using linear models adjusted for tumor stromal content. Results: No differences in methylation were found between adjacent and healthy tissues, but clear differences were found between adjacent and tumor samples. We identified hypermethylated CpG islands located in promoter regions that drive differential gene expression of transcription factors and their target genes. Conclusion: Changes in methylation of a few genes provoke important changes in gene expression, by expanding the signal through transcription activation/repression.

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