scholarly journals Conditional Deletion of Prolyl Hydroxylase Domain-Containing Protein 2 (Phd2) Gene Reveals Its Essential Role in Chondrocyte Function and Endochondral Bone Formation

Endocrinology ◽  
2016 ◽  
Vol 157 (1) ◽  
pp. 127-140 ◽  
Author(s):  
Shaohong Cheng ◽  
Weirong Xing ◽  
Sheila Pourteymoor ◽  
Jan Schulte ◽  
Subburaman Mohan
Keyword(s):  
Bone Formation ◽  
Growth Plate ◽  
Prolyl Hydroxylase ◽  
Conditional Knockout ◽  
Hypertrophic Chondrocytes ◽  
Endochondral Bone Formation ◽  
Bone Surface ◽  
Endochondral Bone ◽  
Prolyl Hydroxylase Domain

Abstract The hypoxic growth plate cartilage requires hypoxia-inducible factor (HIF)-mediated pathways to maintain chondrocyte survival and differentiation. HIF proteins are tightly regulated by prolyl hydroxylase domain-containing protein 2 (Phd2)-mediated proteosomal degradation. We conditionally disrupted the Phd2 gene in chondrocytes by crossing Phd2 floxed mice with type 2 collagen-α1-Cre transgenic mice and found massive increases (>50%) in the trabecular bone mass of long bones and lumbar vertebra of the Phd2 conditional knockout (cKO) mice caused by significant increases in trabecular number and thickness and reductions in trabecular separation. Cortical thickness and tissue mineral density at the femoral middiaphysis of the cKO mice were also significantly increased. Dynamic histomorphometric analyses revealed increased longitudinal length and osteoid surface per bone surface in the primary spongiosa of the cKO mice, suggesting elevated conversion rate from hypertrophic chondrocytes to mineralized bone matrix as well as increased bone formation in the primary spongiosa. In the secondary spongiosa, bone formation measured by mineralizing surface per bone surface and mineral apposition rate were not changed, but resorption was slightly reduced. Increases in the mRNA levels of SRY (sex determining region Y)-box 9, osterix (Osx), type 2 collagen, aggrecan, alkaline phosphatase, bone sialoprotein, vascular endothelial growth factor, erythropoietin, and glycolytic enzymes in the growth plate of cKO mice were detected by quantitative RT-PCR. Immunohistochemistry revealed an increased HIF-1α protein level in the hypertrophic chondrocytes of cKO mice. Infection of chondrocytes isolated from Phd2 floxed mice with adenoviral Cre resulted in similar gene expression patterns as observed in the cKO growth plate chondrocytes. Our findings indicate that Phd2 suppresses endochondral bone formation, in part, via HIF-dependent mechanisms in mice.

scholarly journals Galectin-3 Is a Downstream Regulator of Matrix Metalloproteinase-9 Function during Endochondral Bone Formation

2005 ◽  
Vol 16 (6) ◽  
pp. 3028-3039 ◽  
Author(s):  
Nathalie Ortega ◽  
Danielle J. Behonick ◽  
Céline Colnot ◽  
Douglas N.W. Cooper ◽  
Zena Werb
Keyword(s):  
Bone Formation ◽  
Matrix Metalloproteinase ◽  
Growth Plate ◽  
Matrix Metalloproteinase 9 ◽  
Hypertrophic Chondrocytes ◽  
Endochondral Bone Formation ◽  
Endochondral Bone ◽  
Chondrocyte Death ◽  
Galectin 3 ◽  
Metalloproteinase 9

Endochondral bone formation is characterized by the progressive replacement of a cartilage anlagen by bone at the growth plate with a tight balance between the rates of chondrocyte proliferation, differentiation, and cell death. Deficiency of matrix metalloproteinase-9 (MMP-9) leads to an accumulation of late hypertrophic chondrocytes. We found that galectin-3, an in vitro substrate of MMP-9, accumulates in the late hypertrophic chondrocytes and their surrounding extracellular matrix in the expanded hypertrophic cartilage zone. Treatment of wild-type embryonic metatarsals in culture with full-length galectin-3, but not galectin-3 cleaved by MMP-9, mimicked the embryonic phenotype of Mmp-9 null mice, with an increased hypertrophic zone and decreased osteoclast recruitment. These results indicate that extracellular galectin-3 could be an endogenous substrate of MMP-9 that acts downstream to regulate hypertrophic chondrocyte death and osteoclast recruitment during endochondral bone formation. Thus, the disruption of growth plate homeostasis in Mmp-9 null mice links galectin-3 and MMP-9 in the regulation of the clearance of late chondrocytes through regulation of their terminal differentiation.

scholarly journals Association of an extracellular protein (chondrocalcin) with the calcification of cartilage in endochondral bone formation.

1984 ◽  
Vol 98 (1) ◽  
pp. 54-65 ◽  
Author(s):  
A R Poole ◽  
I Pidoux ◽  
A Reiner ◽  
H Choi ◽  
L C Rosenberg
Keyword(s):  
Extracellular Matrix ◽  
Bone Formation ◽  
Growth Plate ◽  
Calcium Binding ◽  
Calcium Binding Protein ◽  
Cartilage Matrix ◽  
Hypertrophic Chondrocytes ◽  
Endochondral Bone Formation ◽  
Endochondral Bone ◽  
Nucleation Sites

We examined bovine fetal epiphyseal and growth plate cartilages by immunofluorescence microscopy and immunoelectron microscopy using monospecific antibodies to a newly discovered cartilage-matrix calcium-binding protein that we now call chondrocalcin. Chondrocalcin was evenly distributed at relatively low concentration in resting fetal epiphyseal cartilage. In growth plate cartilage, it was absent from the extracellular matrix in the zone of proliferating chondrocytes but was present in intracellular vacuoles in proliferating, maturing and upper hypertrophic chondrocytes. The protein then disappeared from the lower hypertrophic chondrocytes and appeared in the adjoining extracellular matrix, where it was selectively concentrated in the longitudinal septa in precisely the same location where amorphous mineral was deposited in large amounts as demonstrated by von Kossa staining and electron microscopy. Mineral then spread out from these "nucleation sites" to occupy much of the surrounding matrix. Matrix vesicles were identified in this calcifying matrix but they bore no observable morphological relationship to these major sites of calcification where chondrocalcin was concentrated. Since chondrocalcin is a calcium-binding protein and has a strong affinity for hydroxyapatite, these observations suggest that chondrocalcin may play a fundamental role in the creation of nucleation sites for the calcification of cartilage matrix in endochondral bone formation.

Fetal Jaw Movement Affects Condylar Cartilage Development

2005 ◽  
Vol 84 (5) ◽  
pp. 474-479 ◽  
Author(s):  
H. Habib ◽  
T. Hatta ◽  
J. Udagawa ◽  
L. Zhang ◽  
Y. Yoshimura ◽  
...  
Keyword(s):  
Bone Formation ◽  
Mandibular Condyle ◽  
Hypertrophic Chondrocytes ◽  
Endochondral Bone Formation ◽  
Condylar Cartilage ◽  
Mechanical Factor ◽  
Endochondral Bone ◽  
Jaw Movement ◽  
Cartilage Development ◽  
Number Of Cells

Using a mouse exo utero system to examine the effects of fetal jaw movement on the development of condylar cartilage, we assessed the effects of restraint of the animals’ mouths from opening, by suture, at embryonic day (E)15.5. We hypothesized that pre-natal jaw movement is an important mechanical factor in endochondral bone formation of the mandibular condyle. Condylar cartilage was reduced in size, and the bone-cartilage margin was ill-defined in the sutured group at E18.5. Volume, total number of cells, and number of 5-bromo-2′-deoxyuridine-positive cells in the mesenchymal zone were lower in the sutured group than in the non-sutured group at E16.5 and E18.5. Hypertrophic chondrocytes were larger, whereas fewer apoptotic chondrocytes and osteoclasts were observed in the hypertrophic zone in the sutured group at E18.5. Analysis of our data revealed that restricted fetal TMJ movement influences the process of endochondral bone formation of condylar cartilage.

scholarly journals Growth plate expression profiling: Large and small breed dogs provide new insights in endochondral bone formation

2017 ◽  
Author(s):  
Michelle Teunissen ◽  
Frank M. Riemers ◽  
Dik van Leenen ◽  
Marian J. A. Groot Koerkamp ◽  
Björn P. Meij ◽  
...  
Keyword(s):  
Bone Formation ◽  
Growth Plate ◽  
Expression Profiling ◽  
Endochondral Bone Formation ◽  
Endochondral Bone ◽  
Small Breed

scholarly journals Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation

2014 ◽  
Vol 111 (33) ◽  
pp. 12097-12102 ◽  
Author(s):  
L. Yang ◽  
K. Y. Tsang ◽  
H. C. Tang ◽  
D. Chan ◽  
K. S. E. Cheah
Keyword(s):  
Bone Formation ◽  
Hypertrophic Chondrocytes ◽  
Endochondral Bone Formation ◽  
Endochondral Bone

scholarly journals Conditional ablation of MAPK7 expression in chondrocytes impairs endochondral bone formation in limbs and adaptation of chondrocytes to hypoxia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Xiaoming Yang ◽  
Dongmei Zhong ◽  
Wenjie Gao ◽  
Zhiheng Liao ◽  
Yuyu Chen ◽  
...  
Keyword(s):  
Bone Formation ◽  
Growth Plate ◽  
Hypoxia Inducible Factor ◽  
Postnatal Growth ◽  
Mitogen Activated Protein Kinase ◽  
Endochondral Bone Formation ◽  
Adaptation To Hypoxia ◽  
Differentiation Markers ◽  
Endochondral Bone ◽  
Bone Mass Loss

Abstract Background Long bones of limbs are formed through endochondral bone formation, which depends on the coordinated development of growth plates. Our previous studies have demonstrated that dysfunction of mitogen-activated protein kinase 7 (MAPK7) can cause skeletal dysplasia. However, little is known about the role of MAPK7 in the regulation of proliferation and differentiation of chondrocytes during growth plate development. Results Ablation of MAPK7 expression in chondrocytes led to growth restriction, short limbs and bone mass loss in postnatal mice. Histological studies revealed that MAPK7 deficiency increased the apoptosis and decreased the proliferation of chondrocytes in the center of the proliferative layer, where the most highly hypoxic chondrocytes are located. Accordingly, hypertrophic differentiation markers were downregulated in the central hypertrophic layer, beneath the site where abnormal apoptosis was observed. Simultaneously, we demonstrated that hypoxic adaptation and hypoxia-induced activation of hypoxia-inducible factor 1 subunit α (HIF1α) were impaired when MAPK7 could not be activated normally in primary chondrocytes. Concomitantly, vascular invasion into epiphyseal cartilage was inhibited when Mapk7 was deleted. Conclusions We demonstrated that MAPK7 is necessary for maintaining proliferation, survival, and differentiation of chondrocytes during postnatal growth plate development, possibly through modulating HIF1α signaling for adaptation to hypoxia. These results indicate that MAPK7 signaling might be a target for treatment of chondrodysplasia.

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