EphB3 as a potential mediator of developmental and reparative osteogenesis

2021 ◽  
Author(s):  
Rajay A.D. Kamath ◽  
M. Douglas Benson
Keyword(s):  
Tyrosine Kinases ◽  
Bone Growth ◽  
Long Bones ◽  
Bone Homeostasis ◽  
Trabecular Thickness ◽  
Skeletal Patterning ◽  
Trabecular Density ◽  
Membrane Bound ◽  
Stem Cell Niches ◽  
Candidate Regulator

The ephrin-B family of membrane-bound ligands is involved in skeletal patterning, osteogenesis, and bone homeostasis. Yet, despite the increasing collection of data affirming their importance in bone, the Eph tyrosine kinases that serve as the receptors for these ephrins in osteoblast stem cell niches remain unidentified. Here we report the expression of EphB3 at sites of bone growth in the embryo, especially at the calvaria suture fronts, periosteum, chondrocytes and trabeculae of developing long bones. Strong EphB3 expression persisted in the adult calvarial sutures and in the proliferative chondrocytes of long bones, both of which are documented niches for osteoblastic stem cells. We observed EphB3-positive cells in the tissue filling a created calvarial injury, further implying EphB3 involvement in bone healing. Genetic knockout of EphB3 caused an increase in the bone tissue volume as a fraction of total volume in six-week old calvaria and in femoral trabecular density, compared to wild type controls. This difference resolved by twelve weeks of age, when we instead observed an increase in the bone volume of femoral trabeculae and in trabecular thickness. Our data identify EphB3 as a candidate regulator of osteogenesis either alone or in combination with other bone-expressed Ephs, and indicate that it appears to function as a limiter of bone growth.

Longitudinal bone growth in vitro: effects of insulin-like growth factor I and growth hormone

1991 ◽  
Vol 124 (5) ◽  
pp. 602-607 ◽  
Author(s):  
Ben A. A. Scheven ◽  
Nicola J. Hamilton
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Bone Growth ◽  
Long Bone ◽  
Long Bones ◽  
Insulin Like Growth Factor ◽  
Serum Free ◽  
Factor I ◽  
Igf I

Abstract. Longitudinal growth was studied using an in vitro model system of intact rat long bones. Metatarsal bones from 18- and 19-day-old rat fetuses, entirely (18 days) or mainly (19 days) composed of chondrocytes, showed a steady rate of growth and radiolabelled thymidine incorporation for at least 7 days in serum-free media. Addition of recombinant human insulin-like growth factor-I to the culture media resulted in a direct stimulation of the longitudinal growth. Recombinant human growth hormone was also able to stimulate bone growth, although this was generally accomplished after a time lag of more than 2 days. A monoclonal antibody to IGF-I abolished both the IGF-I and GH-stimulated growth. However, the antibody had no effect on the growth of the bone explants in control, serum-free medium. Unlike the fetal long bones, bones from 2-day-old neonatal rats were arrested in their growth after 1-2 days in vitro. The neonatal bones responded to IGF-I and GH in a similar fashion as the fetal bones. Thus in this study in vitro evidence of a direct effect of GH on long bone growth via stimulating local production of IGF by the growth plate chondrocytes is presented. Furthermore, endogenous growth factors, others than IGFs, appear to play a crucial role in the regulation of fetal long bone growth.

scholarly journals Exposure to the RXR agonist SR11237 in early life causes disturbed skeletal morphogenesis in a rat model

2019 ◽  
Author(s):  
Holly Dupuis ◽  
Michael Andrew Pest ◽  
Ermina Hadzic ◽  
Thin Xuan Vo ◽  
Daniel B. Hardy ◽  
...  
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Long Bone ◽  
Tunel Staining ◽  
Long Bones ◽  
Micro Computed Tomography ◽  
Computed Tomography Scanning ◽  
Calcified Tissue ◽  
Trap Staining ◽  
Tomography Scanning

AbstractLongitudinal bone growth occurs through endochondral ossification (EO), controlled by various signaling molecules. Retinoid X Receptor (RXR) is a nuclear receptor with important roles in cell death, development, and metabolism. However, little is known about its role in EO. In this study, the agonist SR11237 was used to evaluate RXR activation on EO.Rats given SR11237 from post-natal day 5 to 15 were harvested for micro-computed tomography scanning and histology. In parallel, newborn CD1 mouse tibiae were cultured with increasing concentrations of SR11237 for histological and whole mount evaluation.RXR agonist-treated rats were smaller than controls, and developed dysmorphia of the growth plate. Cells invading the calcified and dysmorphic growth plate appeared pre-hypertrophic in size and shape corresponding with P57 immunostaining. Additionally, SOX9 positive cells were found surrounding the calcified tissue. The epiphysis of SR11237 treated bones showed increased TRAP staining, and additional TUNEL staining at the osteo-chondral junction. MicroCT revealed morphological disorganization in the long bones of treated animals. Isolated mouse long bones treated with SR11237 grew significantly less than their DMSO controls.This study demonstrates that stimulation of the RXR receptor causes irregular ossification, premature closure of the growth plate, and disrupted long bone growth in rodent models.

NOVEL QUANTIFICATION OF TRABECULAR DENSITY AND TRABECULAR THICKNESS IN THE PROXIMAL FEMUR OF POSTMENOPAUSAL WOMEN.

2007 ◽  
Vol 55 (1) ◽  
pp. S80
Author(s):  
N. K. Hetzer ◽  
A. Favia ◽  
R. K. Rude ◽  
A. Nattiv ◽  
A. Lomovtsev ◽  
...  
Keyword(s):  
Postmenopausal Women ◽  
Proximal Femur ◽  
Trabecular Thickness ◽  
Trabecular Density

Bone and muscle development in three inbred female mouse strains

2021 ◽  
Author(s):  
Ursula Föger-Samwald ◽  
Maria Papageorgiou ◽  
Katharina Wahl-Figlash ◽  
Katharina Kerschan-Schindl ◽  
Peter Pietschmann
Keyword(s):  
Trabecular Bone ◽  
Muscle Development ◽  
Bone Growth ◽  
Volume Fraction ◽  
Bone Structure ◽  
Bone Development ◽  
Mouse Strains ◽  
Structural Reorganization ◽  
Bone Volume Fraction ◽  
Trabecular Thickness

AbstractMuscle force is thought to be one of the main determinants of bone development. Hence, peak muscle growth is expected to precede peak bone growth. In this study, we investigated muscle and bone development in female C57BL/6 J, DBA/2JRj, and C3H/HeOuJ mice. Femoral cortical and trabecular bone structure and the weights of selected muscles were assessed at the ages of 8, 16, and 24 weeks. Muscle mass increased from 8 to 24 weeks in all 3 strains, suggesting peak muscle development at 24 weeks or later. Bone volume fraction, trabecular number, and connectivity density of the femur decreased or remained unchanged, whereas trabecular density and trabecular thickness largely increased. These results suggest a peak in trabecular bone accrual at 8 weeks or earlier followed by further increases in density and structural reorganization of trabeculae. Cortical density, cortical thickness, and cortical cross sectional area increased over time, suggesting a peak in cortical bone accrual at 24 weeks or later. In conclusion, our data provide evidence that growth of muscle lags behind trabecular bone accrual.

scholarly journals Constitutive Activation of β-Catenin in Differentiated Osteoclasts Induces Bone Loss in Mice

2018 ◽  
Vol 48 (5) ◽  
pp. 2091-2102 ◽  
Author(s):  
Xin Sui ◽  
Shijian Deng ◽  
Mengmeng Liu ◽  
Linlin Fan ◽  
Yunfei Wang ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Bone Growth ◽  
Osteoclast Differentiation ◽  
Marker Genes ◽  
Tartrate Resistant Acid Phosphatase ◽  
Bone Homeostasis ◽  
Micro Computed Tomography ◽  
Constitutive Activation

Background/Aims: Activation of the Wnt/β-catenin signalling pathway has been widely investigated in bone biology and shown to promote bone formation. However, its specific effects on osteoclast differentiation have not been fully elucidated. Our study aimed to identify the role of β-catenin in osteoclastogenesis and bone homeostasis. Methods: In the present study, exon 3 in the β-catenin gene (Ctnnb1) allele encoding phosphorylation target serine/threonine residues was flanked by floxP sequences. We generated mice exhibiting conditional β-catenin activation (Ctsk-Cre;Ctnnb1flox(exon3)/+, designated CA-β-catenin) by crossing Ctnnb1flox(exon3)/flox(exon3) mice with osteoclast-specific Ctsk-Cre mice. Bone growth and bone mass were analysed by micro-computed tomography (micro-CT) and histomorphometry. To further examine osteoclast activity, osteoclasts were induced from bone marrow monocytes (BMMs) isolated from CA-β-catenin and Control mice in vitro. Osteoclast differentiation was detected by tartrate-resistant acid phosphatase (TRAP) staining, immunofluorescence staining and reverse transcription-quantitative PCR (RT–qPCR) analysis. Results: Growth retardation and low bone mass were observed in CA-β-catenin mice. Compared to controls, CA-β-catenin mice had significantly reduced trabecular bone numbers under growth plates as well as thinner cortical bones. Moreover, increased TRAP-positive osteoclasts were observed on the surfaces of trabecular bones and cortical bones in the CA-β-catenin mice; consistent results were observed in vitro. In the CA-β-catenin group, excessive numbers of osteoclasts were induced from BMMs, accompanied by the increased expression of osteoclast-associated marker genes. Conclusion: These results indicated that the constitutive activation of β-catenin in osteoclasts promotes osteoclast formation, resulting in bone loss.

scholarly journals Fibroblast Growth Factor Receptor-Mediated Rescue of x-Ephrin B1-Induced Cell Dissociation in XenopusEmbryos

2000 ◽  
Vol 20 (2) ◽  
pp. 724-734 ◽  
Author(s):  
Lisa D. Chong ◽  
Eui Kyun Park ◽  
Erin Latimer ◽  
Robert Friesel ◽  
Ira O. Daar
Keyword(s):  
Cell Adhesion ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Cell Adhesion And Migration ◽  
Membrane Bound ◽  
And Migration

ABSTRACT The Eph family of receptor tyrosine kinases and their membrane-bound ligands, the ephrins, have been implicated in regulating cell adhesion and migration during development by mediating cell-to-cell signaling events. Genetic evidence suggests that ephrins may transduce signals and become tyrosine phosphorylated during embryogenesis. However, the induction and functional significance of ephrin phosphorylation is not yet clear. Here, we report that when we used ectopically expressed proteins, we found that an activated fibroblast growth factor (FGF) receptor associated with and induced the phosphorylation of ephrin B1 on tyrosine. Moreover, this phosphorylation reduced the ability of overexpressed ephrin B1 to reduce cell adhesion. In addition, we identified a region in the cytoplasmic tail of ephrin B1 that is critical for interaction with the FGF receptor; we also report FGF-induced phosphorylation of ephrins in a neural tissue. This is the first demonstration of communication between the FGF receptor family and the Eph ligand family and implicates cross talk between these two cell surface molecules in regulating cell adhesion.

scholarly journals Differences in Shedding of the Interleukin-11 Receptor by the Proteases ADAM9, ADAM10, ADAM17, Meprin α, Meprin β and MT1-MMP

2019 ◽  
Vol 20 (15) ◽  
pp. 3677 ◽  
Author(s):  
Sammel ◽  
Peters ◽  
Lokau ◽  
Scharfenberg ◽  
Werny ◽  
...  
Keyword(s):  
Biologically Active ◽  
Target Cells ◽  
Matrix Metalloprotease ◽  
Bone Homeostasis ◽  
Inflammatory Conditions ◽  
Stat3 Phosphorylation ◽  
Membrane Bound ◽  
The Difference ◽  
Membrane Type ◽  
Interleukin 11

Interleukin-11 (IL-11) has been associated with inflammatory conditions, bone homeostasis, hematopoiesis, and fertility. So far, these functions have been linked to classical IL-11 signaling via the membrane bound receptor (IL-11R). However, a signaling cascade via the soluble IL-11R (sIL-11R), generated by proteolytic cleavage, can also be induced. This process is called IL-11 trans-signaling. A disintegrin and metalloprotease 10 (ADAM10) and neutrophil elastase were described as ectodomain sheddases of the IL-11R, thereby inducing trans-signaling. Furthermore, previous studies employing approaches for the stimulation and inhibition of endogenous ADAM-proteases indicated that ADAM10, but not ADAM17, can cleave the IL-11R. Herein, we show that several metalloproteases, namely ADAM9, ADAM10, ADAM17, meprin β, and membrane-type 1 matrix metalloprotease/matrix metalloprotease-14 (MT1-MMP/MMP-14) when overexpressed are able to shed the IL-11R. All sIL-11R ectodomains were biologically active and capable of inducing signal transducer and activator of transcription 3 (STAT3) phosphorylation in target cells. The difference observed for ADAM10/17 specificity compared to previous studies can be explained by the different approaches used, such as stimulation of protease activity or making use of cells with genetically deleted enzymes.

scholarly journals Relationship between bone growth rate and the thickness of calcified cartilage in the long bones of the Galloanserae (Aves)

2005 ◽  
Vol 206 (5) ◽  
pp. 445-452 ◽  
Author(s):  
L. Montes ◽  
E. de Margerie ◽  
J. Castanet ◽  
A. de Ricqles ◽  
J. Cubo
Keyword(s):  
Growth Rate ◽  
Bone Growth ◽  
Long Bones ◽  
Calcified Cartilage

Les marques de croissance des os et des écailles comme indicateur de l'âge chez Testudo hermanni et Testudo graeca (Reptilia, Chelonia, Testudinidae)

1979 ◽  
Vol 57 (8) ◽  
pp. 1649-1665 ◽  
Author(s):  
Jacques Castanet ◽  
Marc Cheylan
Keyword(s):  
Sexual Maturity ◽  
Bone Growth ◽  
Age Determination ◽  
Close Correlation ◽  
Long Bones ◽  
Histological Observation ◽  
Growth Rings ◽  
Testudo Graeca ◽  
Testudo Hermanni ◽  
Males And Females

This work shows the value of osseous growth marks for age determination in two terrestrial chelonia, Testudo hermanni and Testudo graeca. Careful histological observation of long bones proves that concentric rings show a yearly growth pattern; we have already described similar findings in amphibians, snakes, and lizards.We confirm these data first by the observation of some wild turtles of known age and of a close correlation between the number of bone rings and the number of rings on the cornified scutes. We also confirm in both species that scutes have a yearly growth rhythm and we conclude that bone growth marks provide a good criterion for age determination. Resorption destroys some juvenile rings; we propose a calculation to evaluate the number of resorbed lines to obtain the true individual age.In our turtles, scute growth rings allowed age determination until sexual maturity. With osseous growth marks, we were able to extend accurate ageing until the 20th year. We also established that sexual maturity occurs when animals are 12 or 13 years old in both species, with little difference between males and females.

scholarly journals Sex- and bone-specific responses in bone structure to exogenous leptin and leptin receptor antagonism in the ovine fetus

2018 ◽  
Vol 314 (6) ◽  
pp. R781-R790 ◽  
Author(s):  
Miles J. De Blasio ◽  
Stuart A. Lanham ◽  
Dominique Blache ◽  
Richard O. C. Oreffo ◽  
Abigail L. Fowden ◽  
...  
Keyword(s):  
Growth And Development ◽  
Bone Growth ◽  
Leptin Receptor ◽  
Bone Structure ◽  
Lumbar Vertebrae ◽  
Late Gestation ◽  
Trabecular Thickness ◽  
Receptor Antagonism ◽  
Treatment Groups ◽  
Ovine Fetus

Widespread expression of leptin and its receptor in developing cartilage and bone suggests that leptin may regulate bone growth and development in the fetus. Using microcomputed tomography, this study investigated the effects of exogenous leptin and leptin receptor antagonism on aspects of bone structure in the sheep fetus during late gestation. From 125 to 130 days of gestation (term ~145 days), chronically catheterized singleton sheep fetuses were infused intravenously for 5 days with either saline (0.9% saline, n = 13), recombinant ovine leptin at two doses (0.6 mg·kg−1·day−1 LEP1, n = 10 or 1.4 mg·kg−1·day−1 LEP2, n = 7), or recombinant superactive ovine leptin receptor antagonist (4.6 mg·kg−1·day−1 SOLA, n = 6). No significant differences in plasma insulin-like growth factor-I, osteocalcin, calcium, inorganic phosphate, or alkaline phosphatase were observed between treatment groups. Total femur midshaft diameter and metatarsal lumen diameter were narrower in male fetuses treated with exogenous leptin. In a fixed length of femur midshaft, total and bone volumes were reduced by the higher dose of leptin; nonbone space volume was lower in both groups of leptin-treated fetuses. Leptin infusion caused increments in femur porosity and connectivity density, and vertebral trabecular thickness. Leptin receptor antagonism decreased trabecular spacing and increased trabecular number, degree of anisotrophy, and connectivity density in the lumbar vertebrae. The increase in vertebral porosity observed following leptin receptor antagonism was greater in the malecompared with female, fetuses. Therefore, leptin may have a role in the growth and development of the fetal skeleton, dependent on the concentration of leptin, sex of the fetus, and bone type examined.

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