scholarly journals Essential Role of Hypertrophic Chondrocytes in Endochondral Bone Development

2004 ◽  
Vol 51 (1) ◽  
pp. 19-24 ◽  
Author(s):  
Ung-Il CHUNG
Keyword(s):  
Essential Role ◽  
Bone Development ◽  
Hypertrophic Chondrocytes ◽  
Endochondral Bone

scholarly journals Reversing the miRNA -5p/-3p stoichiometry reveals physiological roles and targets of miR-140 miRNAs

2021 ◽  
Author(s):  
Cameron J Young ◽  
Melissa Caffrey ◽  
Christopher Janton ◽  
Tatsuya Kobayashi
Keyword(s):  
Untranslated Region ◽  
Bone Growth ◽  
Bone Development ◽  
Sequencing Analysis ◽  
Endochondral Bone ◽  
Chondrocyte Maturation ◽  
Protein Loading ◽  
Argonaute Proteins

The chondrocyte specific miR-140 miRNAs are necessary for normal endochondral bone growth in mice. miR-140 deficiency causes dwarfism and craniofacial deformity. However, the physiologically important targets of miR-140 miRNAs are still unclear. The miR-140 gene (Mir140) encodes three chondrocyte-specific microRNAs, miR-140-5p, derived from the 5′ strand of primary miR-140, and miR140-3p.1 and -3p.2, derived from the 3′ strand of primary miR-140. miR-140-3p miRNAs are ten times more abundant than miR-140-5p likely due to the non-preferential loading of miR-140-5p to Argonaute proteins. To differentiate the role of miR-140-5p and -3p miRNAs in endochondral bone development, two distinct mouse models, miR140-C>T, in which the first nucleotide of miR-140-5p was altered from cytosine to uridine, and miR140-CG, where the first two nucleotides of miR-140-3p were changed to cytosine and guanine, were created. These changes are expected to alter Argonaute protein loading preference of -5p and -3p to increase -5p loading and decrease -3p loading without changing the function of miR140-5p. These models presented a mild delay in epiphyseal development with delayed chondrocyte maturation. Using RNA-sequencing analysis of the two models, direct targets of miR140-5p, including Wnt11, were identified. Disruption of the predicted miR140-5p binding site in the 3′ untranslated region of Wnt11 was shown to increase Wnt11 mRNA expression and caused a modest acceleration of epiphyseal development. These results show that the relative abundance of miRNA-5p and -3p can be altered by changing the first nucleotide of miRNAs in vivo, and this method can be useful to identify physiologically important miRNA targets.

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 Expression and localization of activin receptors during endochondral bone development

2001 ◽  
pp. 63-71 ◽  
Author(s):  
M Funaba ◽  
K Ogawa ◽  
M Abe
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Bone Development ◽  
Demineralized Bone Matrix ◽  
Bone Matrix ◽  
Hypertrophic Chondrocytes ◽  
Bone Modeling ◽  
Type I ◽  
Type Ii ◽  
Endochondral Bone ◽  
Activin Receptors

The expression and localization of activins (dimeric protein of inhibin beta subunit) and activin receptors in skeletal tissue were examined. RT-PCR revealed that cultured chondrocytes expressed mRNAs of inhibin/activin betaA and four activin receptors (two type I (ActRI and ActRIB) and two type II (ActRII and ActRIIB)). Immunohistochemical analyses showed that activin betaA, ActRI and ActRII were localized in proliferating chondrocytes and osteoblasts in tibiae of neonatal rats, and in implants of demineralized bone matrix, a well-established model of ectopic bone formation. The immunoreactivities of osteoblasts were decreased with aging in the tibiae and with progressing endochondral bone development in the implants. The strong expression of ActRI was also detected in hypertrophic chondrocytes both in the tibial growth plate and in the implants, whereas immunoreactive ActRII was lower in hypertrophic chondrocytes. Western blot analysis also showed that immunoreactive ActRI, migrating at 52 kDa, was detected only in the implants on days 9 and 11, the period of conversion from cartilage to bone. In view of the sharing of type II receptors between activins and bone morphogenetic proteins (BMPs), our findings suggest that activin/BMP activity involves in bone modeling, especially during active chondro- and osteogenesis and during the conversion from cartilage to bone.

scholarly journals Absence of transcription factor c-maf causes abnormal terminal differentiation of hypertrophic chondrocytes during endochondral bone development

2003 ◽  
Vol 262 (1) ◽  
pp. 51-63 ◽  
Author(s):  
Helen E MacLean ◽  
James I Kim ◽  
Melvin J Glimcher ◽  
Jinxi Wang ◽  
Henry M Kronenberg ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Bone Development ◽  
Terminal Differentiation ◽  
Hypertrophic Chondrocytes ◽  
Endochondral Bone ◽  
Factor C

scholarly journals Raf Kinases Are Essential for Phosphate Induction of ERK1/2 Phosphorylation in Hypertrophic Chondrocytes and Normal Endochondral Bone Development

2017 ◽  
Vol 292 (8) ◽  
pp. 3164-3171 ◽  
Author(s):  
Garyfallia Papaioannou ◽  
Elizabeth T. Petit ◽  
Eva S. Liu ◽  
Manuela Baccarini ◽  
Catrin Pritchard ◽  
...  
Keyword(s):  
Growth Plate ◽  
Vascular Invasion ◽  
Bone Development ◽  
Skeletal Development ◽  
Hypertrophic Chondrocytes ◽  
Chondrocyte Apoptosis ◽  
Caspase 9 ◽  
Endochondral Bone ◽  
Hypertrophic Chondrocyte

Hypophosphatemia causes rickets by impairing hypertrophic chondrocyte apoptosis. Phosphate induction of MEK1/2-ERK1/2 phosphorylation in hypertrophic chondrocytes is required for phosphate-mediated apoptosis and growth plate maturation. MEK1/2 can be activated by numerous molecules including Raf isoforms. A- and B-Raf ablation in chondrocytes does not alter skeletal development, whereas ablation of C-Raf decreases hypertrophic chondrocyte apoptosis and impairs vascularization of the growth plate. However, ablation of C-Raf does not impair phosphate-induced ERK1/2 phosphorylation in vitro, but leads to rickets by decreasing VEGF protein stability. To determine whether Raf isoforms are required for phosphate-induced hypertrophic chondrocyte apoptosis, mice lacking all three Raf isoforms in chondrocytes were generated. Raf deletion caused neonatal death and a significant expansion of the hypertrophic chondrocyte layer of the growth plate, accompanied by decreased cleaved caspase-9. This was associated with decreased phospho-ERK1/2 immunoreactivity in the hypertrophic chondrocyte layer and impaired vascular invasion. These data further demonstrated that Raf kinases are required for phosphate-induced ERK1/2 phosphorylation in cultured hypertrophic chondrocytes and perform essential, but partially redundant roles in growth plate maturation.

scholarly journals The role of histone deacetylase 4 during chondrocyte hypertrophy and endochondral bone development

2020 ◽  
Vol 9 (2) ◽  
pp. 82-89 ◽  
Author(s):  
Zhi Chen ◽  
Zhiwei Zhang ◽  
Li Guo ◽  
Xiaochun Wei ◽  
Yang Zhang ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Bone Development ◽  
Chromatin Condensation ◽  
Negative Regulator ◽  
Endochondral Bone Formation ◽  
Endochondral Bone ◽  
Chondrocyte Hypertrophy ◽  
Histone Deacetylase 4

Chondrocyte hypertrophy represents a crucial turning point during endochondral bone development. This process is tightly regulated by various factors, constituting a regulatory network that maintains normal bone development. Histone deacetylase 4 (HDAC4) is the most well-characterized member of the HDAC class IIa family and participates in different signalling networks during development in various tissues by promoting chromatin condensation and transcriptional repression. Studies have reported that HDAC4-null mice display premature ossification of developing bones due to ectopic and early-onset chondrocyte hypertrophy. Overexpression of HDAC4 in proliferating chondrocytes inhibits hypertrophy and ossification of developing bones, which suggests that HDAC4, as a negative regulator, is involved in the network regulating chondrocyte hypertrophy. Overall, HDAC4 plays a key role during bone development and disease. Thus, understanding the role of HDAC4 during chondrocyte hypertrophy and endochondral bone formation and its features regarding the structure, function, and regulation of this process will not only provide new insight into the mechanisms by which HDAC4 is involved in chondrocyte hypertrophy and endochondral bone development, but will also create a platform for developing a therapeutic strategy for related diseases. Cite this article: Bone Joint Res. 2020;9(2):82–89.

Delta-1 negatively regulates the transition from prehypertrophic to hypertrophic chondrocytes during cartilage formation

Development ◽  
1999 ◽  
Vol 126 (5) ◽  
pp. 987-998 ◽  
Author(s):  
R. Crowe ◽  
J. Zikherman ◽  
L. Niswander
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Bone Development ◽  
Hypertrophic Chondrocytes ◽  
Signaling System ◽  
Endochondral Bone ◽  
Cell Fate Decisions ◽  
Cartilage Formation ◽  
Chondrocyte Maturation

Endochondral bone development begins with the formation of a cartilage template. Chondrocytes within this template undergo a progressive program of maturation from proliferative to prehypertrophic chondrocytes to hypertrophic chondrocytes. The progression of cells through these steps of differentiation must be carefully controlled to ensure coordinated growth. Because the Delta/Notch signaling system is known to regulate cell fate choices, we sought to determine if these molecules might be involved in the progressive cell fate decisions that chondocytes undergo. Here we demonstrate in the chick that Delta/Notch signaling negatively regulates progression from the prehypertrophic to hypertrophic state of differentiation. Delta-1 is expressed specifically in the hypertrophic chondrocytes while Notch-2 is expressed in chondrocytes at all stages. Misexpression of Delta-1 using a replication-competent retrovirus blocks chondrocyte maturation. Prehypertrophic cells form normally but do not undergo differentiation to hypertrophic cells, resulting in shortened skeletal elements that lack ossification. We conclude that Delta-1 acts during chondrogenesis to inhibit the transition from prehypertrophic chondrocytes to hypertrophic chondrocytes, thus defining a novel mechanism for the regulation of the chondrocyte maturation program. In addition, these results reveal a new role for Delta/Notch signaling in regulating the progression to a terminally differentiated state.

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