EXT1 regulates chondrocyte proliferation and differentiation during endochondral bone development

Bone ◽  
2005 ◽  
Vol 36 (3) ◽  
pp. 379-386 ◽  
Author(s):  
Matthew J. Hilton ◽  
Laura Gutiérrez ◽  
Daniel A. Martinez ◽  
Dan E. Wells
Keyword(s):  
Bone Development ◽  
Chondrocyte Proliferation ◽  
Endochondral Bone ◽  
Proliferation And Differentiation

Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation

Development ◽  
2001 ◽  
Vol 128 (24) ◽  
pp. 5099-5108 ◽  
Author(s):  
Fanxin Long ◽  
Xiaoyan M. Zhang ◽  
Seth Karp ◽  
Yingzi Yang ◽  
Andrew P. McMahon
Keyword(s):  
Cyclin D1 ◽  
Hedgehog Signaling ◽  
Genetic Manipulation ◽  
Bone Development ◽  
Transmembrane Protein ◽  
Wild Type ◽  
Chondrocyte Proliferation ◽  
Direct Role ◽  
Endochondral Bone ◽  
Proliferation And Differentiation

Indian hedgehog (Ihh), one of the three mammalian hedgehog (Hh) proteins, coordinates proliferation and differentiation of chondrocytes during endochondral bone development. Smoothened (Smo) is a transmembrane protein that transduces all Hh signals. In order to discern the direct versus indirect roles of Ihh in cartilage development, we have used the Cre-loxP approach to remove Smo activity specifically in chondrocytes. Animals generated by this means develop shorter long bones when compared to wild-type littermates. In contrast to Ihh mutants (Ihhn/Ihhn), chondrocyte differentiation proceeds normally. However, like Ihhn/Ihhn mice, proliferation of chondrocytes is reduced by about 50%, supporting a direct role for Ihh in the regulation of chondrocyte proliferation. Moreover, by overexpressing either Ihh or a constitutively active Smo allele (Smo*) specifically in the cartilage using the bigenic UAS-Gal4 system, we demonstrate that activation of the Ihh signaling pathway is sufficient to promote chondrocyte proliferation. Finally, expression of cyclin D1 is markedly downregulated when either Ihh or Smo activity is removed from chondrocytes, indicating that Ihh regulates chondrocyte proliferation at least in part by modulating the transcription of cyclin D1. Taken together, the present study establishes Ihh as a key mitogen in the endochondral skeleton.

scholarly journals BMP2, but not BMP4, is crucial for chondrocyte proliferation and maturation during endochondral bone development

2011 ◽  
Vol 124 (20) ◽  
pp. 3428-3440 ◽  
Author(s):  
B. Shu ◽  
M. Zhang ◽  
R. Xie ◽  
M. Wang ◽  
H. Jin ◽  
...  
Keyword(s):  
Bone Development ◽  
Chondrocyte Proliferation ◽  
Endochondral Bone

scholarly journals A-Raf and B-Raf Are Dispensable for Normal Endochondral Bone Development, and Parathyroid Hormone-Related Peptide Suppresses Extracellular Signal-Regulated Kinase Activation in Hypertrophic Chondrocytes

2007 ◽  
Vol 28 (1) ◽  
pp. 344-357 ◽  
Author(s):  
Sylvain Provot ◽  
Gregory Nachtrab ◽  
Jennifer Paruch ◽  
Adele Pin Chen ◽  
Alcino Silva ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Parathyroid Hormone ◽  
Bone Development ◽  
Hypertrophic Chondrocytes ◽  
Chondrocyte Proliferation ◽  
Endochondral Bone ◽  
Extracellular Signal Regulated Kinase ◽  
Chondrocyte Maturation ◽  
Extracellular Signal ◽  
Parathyroid Hormone Related Peptide

ABSTRACT Parathyroid hormone-related peptide (PTHrP) and the parathyroid hormone-PTHrP receptor increase chondrocyte proliferation and delay chondrocyte maturation in endochondral bone development at least partly through cyclic AMP (cAMP)-dependent signaling pathways. Because data suggest that the ability of cAMP to stimulate cell proliferation involves the mitogen-activated protein kinase kinase kinase B-Raf, we hypothesized that B-Raf might mediate the proliferative action of PTHrP in chondrocytes. Though B-Raf is expressed in proliferative chondrocytes, its conditional removal from cartilage did not affect chondrocyte proliferation and maturation or PTHrP-induced chondrocyte proliferation and PTHrP-delayed maturation. Similar results were obtained by conditionally removing B-Raf from osteoblasts. Because A-raf and B-raf are expressed similarly in cartilage, we speculated that they may fulfill redundant functions in this tissue. Surprisingly, mice with chondrocytes deficient in both A-Raf and B-Raf exhibited normal endochondral bone development. Activated extracellular signal-regulated kinase (ERK) was detected primarily in hypertrophic chondrocytes, where C-raf is expressed, and the suppression of ERK activation in these cells by PTHrP or a MEK inhibitor coincided with a delay in chondrocyte maturation. Taken together, these results demonstrate that B-Raf and A-Raf are dispensable for endochondral bone development and they indicate that the main role of ERK in cartilage is to stimulate not cell proliferation, but rather chondrocyte maturation.

scholarly journals TGFβ and PTHrP Control Chondrocyte Proliferation by Activating Cyclin D1 Expression

2001 ◽  
Vol 12 (12) ◽  
pp. 3852-3863 ◽  
Author(s):  
Frank Beier ◽  
Zenobia Ali ◽  
Dereck Mok ◽  
Allison C. Taylor ◽  
Todd Leask ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Bone Development ◽  
Chondrocyte Proliferation ◽  
Endochondral Bone ◽  
Cycle Progression ◽  
Related Transcription Factor

Exact coordination of growth plate chondrocyte proliferation is necessary for normal endochondral bone development and growth. Here we show that PTHrP and TGFβ control chondrocyte cell cycle progression and proliferation by stimulating signaling pathways that activate transcription from the cyclin D1 promoter. The TGFβ pathway activates the transcription factor ATF-2, whereas PTHrP uses the related transcription factor CREB, to stimulate cyclin D1 promoter activity via the CRE promoter element. Inhibition of cyclin D1 expression with antisense oligonucleotides causes a delay in progression of chondrocytes through the G1 phase of the cell cycle, reduced E2F activity, and decreased proliferation. Growth plates from cyclin D1–deficient mice display a smaller zone of proliferating chondrocytes, confirming the requirement for cyclin D1 in chondrocyte proliferation in vivo. These data identify the cyclin D1 gene as an essential component of chondrocyte proliferation as well as a fundamental target gene of TGFβ and PTHrP during skeletal growth.

The CREB family of activators is required for endochondral bone development

Development ◽  
2001 ◽  
Vol 128 (4) ◽  
pp. 541-550
Author(s):  
F. Long ◽  
E. Schipani ◽  
H. Asahara ◽  
H. Kronenberg ◽  
M. Montminy
Keyword(s):  
Transgenic Mice ◽  
Bone Development ◽  
Dominant Negative ◽  
Endochondral Bone Formation ◽  
Wild Type ◽  
Growth Plate Chondrocytes ◽  
Chondrocyte Proliferation ◽  
Endochondral Bone ◽  
Proliferative Zone ◽  
Distinct Signaling Pathway

We have evaluated the importance of the CREB family of transcriptional activators for endochondral bone formation by expressing a potent dominant negative CREB inhibitor (A-CREB) in growth plate chondrocytes of transgenic mice. A-CREB transgenic mice exhibited short-limbed dwarfism and died minutes after birth, apparently due to respiratory failure from a diminished rib cage circumference. Consistent with the robust Ser133 phosphorylation and, hence, activation of CREB in chondrocytes within the proliferative zone of wild-type cartilage during development, chondrocytes in A-CREB mutant cartilage exhibited a profound decrease in proliferative index and a delay in hypertrophy. Correspondingly, the expression of certain signaling molecules in cartilage, most notably the Indian hedgehog (Ihh) receptor patched (Ptch), was lower in A-CREB expressing versus wild-type chondrocytes. CREB appears to promote Ptch expression in proliferating chondrocytes via an Ihh-independent pathway; phospho-CREB levels were comparable in cartilage from Ihh(−/−) and wild-type mice. These results demonstrate the presence of a distinct signaling pathway in developing bone that potentiates Ihh signaling and regulates chondrocyte proliferation, at least in part, via the CREB family of activators.

scholarly journals Microarray Analyses of Gene Expression during Chondrocyte Differentiation Identifies Novel Regulators of Hypertrophy

2005 ◽  
Vol 16 (11) ◽  
pp. 5316-5333 ◽  
Author(s):  
Claudine G. James ◽  
C. Thomas G. Appleton ◽  
Veronica Ulici ◽  
T. Michael Underhill ◽  
Frank Beier
Keyword(s):  
Gene Expression ◽  
Bone Development ◽  
Skeletal Development ◽  
Expression Patterns ◽  
Chondrocyte Differentiation ◽  
Endochondral Bone ◽  
Temporal Gene Expression ◽  
Affymetrix Microarrays ◽  
Time Period ◽  
And Cluster Analysis

Ordered chondrocyte differentiation and maturation is required for normal skeletal development, but the intracellular pathways regulating this process remain largely unclear. We used Affymetrix microarrays to examine temporal gene expression patterns during chondrogenic differentiation in a mouse micromass culture system. Robust normalization of the data identified 3300 differentially expressed probe sets, which corresponds to 1772, 481, and 249 probe sets exhibiting minimum 2-, 5-, and 10-fold changes over the time period, respectively. GeneOntology annotations for molecular function show changes in the expression of molecules involved in transcriptional regulation and signal transduction among others. The expression of identified markers was confirmed by RT-PCR, and cluster analysis revealed groups of coexpressed transcripts. One gene that was up-regulated at later stages of chondrocyte differentiation was Rgs2. Overexpression of Rgs2 in the chondrogenic cell line ATDC5 resulted in accelerated hypertrophic differentiation, thus providing functional validation of microarray data. Collectively, these analyses provide novel information on the temporal expression of molecules regulating endochondral bone development.

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