scholarly journals Ablation of Ephrin B2 in Col2 Expressing Cells Delays Fracture Repair

Endocrinology ◽  
2020 ◽  
Vol 161 (12) ◽  
Author(s):  
Yongmei Wang ◽  
Lin Ling ◽  
Faming Tian ◽  
Sun Hee Won Kim ◽  
Sunita Ho ◽  
...  
Keyword(s):  
Bone Formation ◽  
Cell Activation ◽  
Bone Development ◽  
Type Ii Collagen ◽  
Fracture Site ◽  
Fracture Repair ◽  
Endochondral Bone Formation ◽  
Endochondral Bone ◽  
Intramembranous Bone ◽  
Endothelial Growth Factor

Abstract Ephrin B2 is critical for endochondral bone development. In this study, we investigated its role in fracture repair by deleting ephrin B2 in type II collagen (Col.2) expressing cells. We used a nonstable tibia fracture model to evaluate fracture repair at 3 sites: intramembranous bone formation, endochondral bone formation, and intramedullary bone formation. We observed that during fracture repair, deletion of ephrin B2 impaired periosteal stem cell activation, inhibited their proliferation, decreased their survival, and blocked their differentiation into osteoblasts and chondrocytes. In addition, deletion of ephrin B2 decreased vascular endothelial growth factor production as well as vascular invasion into the fracture site. These changes led to reduced cartilage to bone conversion in the callus with decreased new bone formation, resulting in impaired fracture repair. Our data indicate that ephrin B2 in Col2-expressing cells is a critical regulator of fracture repair, pointing to a new and potentially targetable mechanism to enhance fracture repair.

scholarly journals Roles of Chondrocytes in Endochondral Bone Formation and Fracture Repair

2016 ◽  
Vol 96 (1) ◽  
pp. 23-30 ◽  
Author(s):  
R.J. Hinton ◽  
Y. Jing ◽  
J. Jing ◽  
J.Q. Feng
Keyword(s):  
Bone Formation ◽  
Fracture Repair ◽  
Endochondral Bone Formation ◽  
Endochondral Bone

scholarly journals Selective Deficiency of the “Bone-related”Runx2-II Unexpectedly Preserves Osteoblast-mediated Skeletogenesis

2004 ◽  
Vol 279 (19) ◽  
pp. 20307-20313 ◽  
Author(s):  
Zhou-Sheng Xiao ◽  
Anita B. Hjelmeland ◽  
L. D. Quarles
Keyword(s):  
Bone Formation ◽  
Ex Vivo ◽  
Mesenchymal Cells ◽  
Endochondral Bone Formation ◽  
Endochondral Bone ◽  
Chondrocyte Maturation ◽  
Intramembranous Bone ◽  
Exon 1 ◽  
Metaphyseal Bone ◽  
Deficient Mice

Runx2 (runt-related transcription factor 2) is a master regulator of skeletogenesis. Distinct promoters in the Runx2 gene transcribe the “bone-related”Runx2-II and non-osseousRunx2-I isoforms that differ only in their respective N termini. Existing mutant mouse models with both isoforms deleted exhibit an arrest of osteoblast and chondrocyte maturation and the complete absence of mineralized bone, but they do not distinguish the separate functions of the two N-terminal isoforms. To elucidate the function of the bone-related isoform, we generated selectiveRunx2-II-deficient mice by the targeted deletion of the distal promoter and exon 1. HomozygousRunx2-II-deficient (Runx2-II-/-) mice unexpectedly formed axial, appendicular, and craniofacial bones derived from either intramembranous ossification or mesenchymal cells of the bone collar, but they failed to form the posterior cranium and other bones derived from endochondral ossification. HeterozygousRunx2-II-deficient mice had grossly normal skeletons, but were osteopenic. The commitment of mesenchymal cellsex vivoto the osteoblast lineage occurred inRunx2-II-/-mice, but osteoblastic gene expression was impaired. Chondrocyte maturation appeared normal, but the zone of hypertrophic chondrocytes was not transformed into metaphyseal bone, leading to widened growth plates inRunx2-II-/-mice. Compensatory increments inRunx2-I expression occurred inRunx2-II-/-mice but were not sufficient to normalize osteoblastic maturation or transcriptional activity. Our findings support distinct functions ofRunx2-II and -I in the control of skeletogenesis.Runx2-I is sufficient for early osteoblastogenesis and intramembranous bone formation, whereasRunx2-II is necessary for complete osteoblastic maturation and endochondral bone formation.

Microarray analysis of gene expression during the inflammation and endochondral bone formation stages of rat femur fracture repair

Bone ◽  
2006 ◽  
Vol 38 (4) ◽  
pp. 521-529 ◽  
Author(s):  
Charles H. Rundle ◽  
Hali Wang ◽  
Hongrun Yu ◽  
Robert B. Chadwick ◽  
Emile I. Davis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Formation ◽  
Microarray Analysis ◽  
Femur Fracture ◽  
Fracture Repair ◽  
Rat Femur ◽  
Endochondral Bone Formation ◽  
Endochondral Bone

scholarly journals Site-1 protease is essential for endochondral bone formation in mice

2007 ◽  
Vol 179 (4) ◽  
pp. 687-700 ◽  
Author(s):  
Debabrata Patra ◽  
Xiaoyun Xing ◽  
Sherri Davies ◽  
Jennifer Bryan ◽  
Carl Franz ◽  
...  
Keyword(s):  
Er Stress ◽  
Hedgehog Signaling ◽  
Endochondral Ossification ◽  
Bone Development ◽  
Active Form ◽  
Type Ii Collagen ◽  
Chondrocyte Apoptosis ◽  
Endochondral Bone Formation ◽  
Endochondral Bone ◽  
Er Stress Response

Site-1 protease (S1P) has an essential function in the conversion of latent, membrane-bound transcription factors to their free, active form. In mammals, abundant expression of S1P in chondrocytes suggests an involvement in chondrocyte function. To determine the requirement of S1P in cartilage and bone development, we have created cartilage-specific S1P knockout mice (S1Pcko). S1Pcko mice exhibit chondrodysplasia and a complete lack of endochondral ossification even though Runx2 expression, Indian hedgehog signaling, and osteoblastogenesis is intact. However, there is a substantial increase in chondrocyte apoptosis in the cartilage of S1Pcko mice. Extraction of type II collagen is substantially lower from S1Pcko cartilage. In S1Pcko mice, the collagen network is disorganized and collagen becomes entrapped in chondrocytes. Ultrastructural analysis reveals that the endoplasmic reticulum (ER) in S1Pcko chondrocytes is engorged and fragmented in a manner characteristic of severe ER stress. These data suggest that S1P activity is necessary for a specialized ER stress response required by chondrocytes for the genesis of normal cartilage and thus endochondral ossification.

scholarly journals Parathyroid hormone-related peptide-depleted mice show abnormal epiphyseal cartilage development and altered endochondral bone formation.

1994 ◽  
Vol 126 (6) ◽  
pp. 1611-1623 ◽  
Author(s):  
N Amizuka ◽  
H Warshawsky ◽  
J E Henderson ◽  
D Goltzman ◽  
A C Karaplis
Keyword(s):  
Bone Formation ◽  
Embryonic Stem ◽  
Type Ii Collagen ◽  
Epiphyseal Plate ◽  
Epiphyseal Cartilage ◽  
Endochondral Bone Formation ◽  
Type Ii ◽  
Endochondral Bone ◽  
Cartilage Development ◽  
Calcified Cartilage

To elucidate the role of PTHrP in skeletal development, we examined the proximal tibial epiphysis and metaphysis of wild-type (PTHrP-normal) 18-19-d-old fetal mice and of chondrodystrophic litter mates homozygous for a disrupted PTHrP allele generated via homologous recombination in embryonic stem cells (PTHrP-depleted). In the PTHrP-normal epiphysis, immunocytochemistry showed PTHrP to be localized in chondrocytes within the resting zone and at the junction between proliferative and hypertrophic zones. In PTHrP-depleted epiphyses, a diminished [3H]thymidine-labeling index was observed in the resting and proliferative zones accounting for reduced numbers of epiphyseal chondrocytes and for a thinner epiphyseal plate. In the mutant hypertrophic zone, enlarged chondrocytes were interspersed with clusters of cells that did not hypertrophy, but resembled resting or proliferative chondrocytes. Although the overall content of type II collagen in the epiphyseal plate was diminished, the lacunae of these non-hypertrophic chondrocytes did react for type II collagen. Moreover, cell membrane-associated chondroitin sulfate immunoreactivity was evident on these cells. Despite the presence of alkaline phosphatase activity on these nonhypertrophic chondrocytes, the adjacent cartilage matrix did not calcify and their persistence accounted for distorted chondrocyte columns and sporadic distribution of calcified cartilage. Consequently, in the metaphysis, bone deposited on the irregular and sparse scaffold of calcified cartilage and resulted in mixed spicules that did not parallel the longitudinal axis of the tibia and were, therefore, inappropriate for bone elongation. Thus, PTHrP appears to modulate both the proliferation and differentiation of chondrocytes and its absence alters the temporal and spatial sequence of epiphyseal cartilage development and of subsequent endochondral bone formation necessary for normal elongation of long bones.

scholarly journals Constitutive E2F1 Overexpression Delays Endochondral Bone Formation by Inhibiting Chondrocyte Differentiation

2003 ◽  
Vol 23 (10) ◽  
pp. 3656-3668 ◽  
Author(s):  
Blanca Scheijen ◽  
Marieke Bronk ◽  
Tiffany van der Meer ◽  
René Bernards
Keyword(s):  
Bone Formation ◽  
Endochondral Ossification ◽  
Bone Growth ◽  
Late Phase ◽  
Type Ii Collagen ◽  
Endochondral Bone Formation ◽  
Nodule Formation ◽  
Chondrocyte Differentiation ◽  
Endochondral Bone ◽  
Chondrocyte Maturation

ABSTRACT Longitudinal bone growth results from endochondral ossification, a process that requires proliferation and differentiation of chondrocytes. It has been shown that proper endochondral bone formation is critically dependent on the retinoblastoma family members p107 and p130. However, the precise functional roles played by individual E2F proteins remain poorly understood. Using both constitutive and conditional E2F1 transgenic mice, we show that ubiquitous transgene-driven expression of E2F1 during embryonic development results in a dwarf phenotype and significantly reduced postnatal viability. Overexpression of E2F1 disturbs chondrocyte maturation, resulting in delayed endochondral ossification, which is characterized by reduced hypertrophic zones and disorganized growth plates. Employing the chondrogenic cell line ATDC5, we investigated the effects of enforced E2F expression on the different phases of chondrocyte maturation that are normally required for endochondral ossification. Ectopic E2F1 expression strongly inhibits early- and late-phase differentiation of ATDC5 cells, accompanied by diminished cartilage nodule formation as well as decreased type II collagen, type X collagen, and aggrecan gene expression. In contrast, overexpression of E2F2 or E2F3a results in only a marginal delay of chondrocyte maturation, and increased E2F4 levels have no effect. These data are consistent with the notion that E2F1 is a regulator of chondrocyte differentiation.

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