Regulation of Long Bone Growth in Vertebrates; It Is Time to Catch Up

Alberto Roselló-Díez; Alexandra L. Joyner

doi:10.1210/er.2015-1048

Cell-nonautonomous local and systemic responses to cell arrest enable long-bone catch-up growth in developing mice

10.1101/218487 ◽

2017 ◽

Cited By ~ 1

Author(s):

Alberto Roselló-Díez ◽

Linda Madisen ◽

Sébastien Bastide ◽

Hongkui Zeng ◽

Alexandra L. Joyner

Keyword(s):

Internal Control ◽

Bone Growth ◽

Systemic Effect ◽

Long Bone ◽

Body Proportions ◽

Compensatory Mechanisms ◽

Left Limb ◽

Catch Up ◽

The Right ◽

Systemic Responses

AbstractCatch-up growth after insults to growing organs is paramount to achieving robust body proportions. In fly larvae, local injury is followed by local and systemic compensatory mechanisms that allow damaged tissues to regain proportions with other tissues. In vertebrates, local catch-up growth has been described after transient reduction of bone growth, but the underlying cellular responses are controversial. We developed an approach to study catch-up growth in foetal mice by inducing mosaic expression of the cell cycle suppressor p21 in the cartilage cells (chondrocytes) that drive long bone elongation. By specifically targeting the left hindlimb, the right limb served as an internal control. Strikingly, left-right limb symmetry was not altered, revealing deployment of compensatory mechanisms. Above a certain threshold of insult, an orchestrated response was triggered involving local enhancement of bone growth and systemic growth reduction that ensured body proportions were maintained. The local response entailed hyper-proliferation of spared left-limb chondrocytes that was associated with reduced chondrocyte density. The systemic effect involved impaired placental IGF signalling and function, revealing bone-placenta communication. Thus, vertebrates, much like invertebrates, can mount coordinated local and systemic responses to developmental insults to ensure normal body proportions are maintained.

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

Acta Endocrinologica ◽

10.1530/acta.0.1240602 ◽

1991 ◽

Vol 124 (5) ◽

pp. 602-607 ◽

Cited By ~ 36

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.

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

10.1101/774851 ◽

2019 ◽

Cited By ~ 2

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.

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Catch-Up Growth after Hypothyroidism Is Caused by Delayed Growth Plate Senescence

Endocrinology ◽

10.1210/en.2007-0993 ◽

2008 ◽

Vol 149 (4) ◽

pp. 1820-1828 ◽

Cited By ~ 32

Author(s):

Rose Marino ◽

Anita Hegde ◽

Kevin M. Barnes ◽

Lenneke Schrier ◽

Joyce A. Emons ◽

...

Keyword(s):

Growth Rate ◽

Growth Inhibition ◽

Growth Plate ◽

Bone Growth ◽

Structural Characteristics ◽

Linear Growth Rate ◽

Growth Plate Chondrocytes ◽

Growth Plates ◽

Catch Up ◽

Growth Inhibiting

Catch-up growth is defined as a linear growth rate greater than expected for age after a period of growth inhibition. We hypothesized that catch-up growth occurs because growth-inhibiting conditions conserve the limited proliferative capacity of growth plate chondrocytes, thus slowing the normal process of growth plate senescence. When the growth-inhibiting condition resolves, the growth plates are less senescent and therefore grow more rapidly than normal for age. To test this hypothesis, we administered propylthiouracil to newborn rats for 8 wk to induce hypothyroidism and then stopped the propylthiouracil to allow catch-up growth. In untreated controls, the growth plates underwent progressive, senescent changes in multiple functional and structural characteristics. We also identified genes that showed large changes in mRNA expression in growth plate and used these changes as molecular markers of senescence. In treated animals, after stopping propylthiouracil, these functional, structural, and molecular senescent changes were delayed, compared with controls. This delayed senescence included a delayed decline in longitudinal growth rate, resulting in catch-up growth. The findings demonstrate that growth inhibition due to hypothyroidism slows the developmental program of growth plate senescence, including the normal decline in the rate of longitudinal bone growth, thus accounting for catch-up growth.

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Rac signaling in osteoblastic cells is required for normal bone development but is dispensable for hematopoietic development

Blood ◽

10.1182/blood-2011-07-368753 ◽

2012 ◽

Vol 119 (3) ◽

pp. 736-744 ◽

Cited By ~ 16

Author(s):

Steven W. Lane ◽

Serena De Vita ◽

Kylie A. Alexander ◽

Ruchan Karaman ◽

Michael D. Milsom ◽

...

Keyword(s):

Bone Growth ◽

Bone Development ◽

Long Bone ◽

Perivascular Niche ◽

Hematopoietic Stem ◽

Hsc Niche ◽

Rac1 Gtpase

Abstract Hematopoietic stem cells (HSCs) interact with osteoblastic, stromal, and vascular components of the BM hematopoietic microenvironment (HM) that are required for the maintenance of long-term self-renewal in vivo. Osteoblasts have been reported to be a critical cell type making up the HSC niche in vivo. Rac1 GTPase has been implicated in adhesion, spreading, and differentiation of osteoblast cell lines and is critical for HSC engraftment and retention. Recent data suggest a differential role of GTPases in endosteal/osteoblastic versus perivascular niche function. However, whether Rac signaling pathways are also necessary in the cell-extrinsic control of HSC function within the HM has not been examined. In the present study, genetic and inducible models of Rac deletion were used to demonstrate that Rac depletion causes impaired proliferation and induction of apoptosis in the OP9 cell line and in primary BM stromal cells. Deletion of Rac proteins caused reduced trabecular and cortical long bone growth in vivo. Surprisingly, HSC function and maintenance of hematopoiesis in vivo was preserved despite these substantial cell-extrinsic changes. These data have implications for therapeutic strategies to target Rac signaling in HSC mobilization and in the treatment of leukemia and provide clarification to our evolving concepts of HSC-HM interactions.

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Automated Segmentation and Object Classification of CT Images: Application toIn VivoMolecular Imaging of Avian Embryos

International Journal of Biomedical Imaging ◽

10.1155/2013/508474 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Alexander Heidrich ◽

Jana Schmidt ◽

Johannes Zimmermann ◽

Hans Peter Saluz

Keyword(s):

Image Analysis ◽

Image Segmentation ◽

Bone Growth ◽

Imaging Techniques ◽

Long Bone ◽

Automated Segmentation ◽

Chick Embryos ◽

In Ovo

Background. Although chick embryogenesis has been studied extensively, there has been growing interest in the investigation of skeletogenesis. In addition to improved poultry health and minimized economic loss, a greater understanding of skeletal abnormalities can also have implications for human medicine. Truein vivostudies require noninvasive imaging techniques such as high-resolution microCT. However, the manual analysis of acquired images is both time consuming and subjective.Methods. We have developed a system for automated image segmentation that entails object-based image analysis followed by the classification of the extracted image objects. For image segmentation, a rule set was developed using Definiens image analysis software. The classification engine was implemented using the WEKA machine learning tool.Results. Our system reduces analysis time and observer bias while maintaining high accuracy. Applying the system to the quantification of long bone growth has allowed us to present the first truein ovodata for bone length growth recorded in the same chick embryos.Conclusions. The procedures developed represent an innovative approach for the automated segmentation, classification, quantification, and visualization of microCT images. MicroCT offers the possibility of performing longitudinal studies and thereby provides unique insights into the morpho- and embryogenesis of live chick embryos.

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Altered paracrine signaling from the injured knee joint impairs postnatal long bone growth

eLife ◽

10.7554/elife.27210 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 6

Author(s):

Alberto Roselló-Díez ◽

Daniel Stephen ◽

Alexandra L Joyner

Keyword(s):

Knee Joint ◽

Internal Control ◽

Bone Growth ◽

Long Bone ◽

Paracrine Signaling ◽

Growth Modulation ◽

Genetic Mouse Model ◽

Mesenchyme Cells ◽

Injured Knee ◽

The Right

Regulation of organ growth is a poorly understood process. In the long bones, the growth plates (GPs) drive elongation by generating a scaffold progressively replaced by bone. Although studies have focused on intrinsic GP regulation, classic and recent experiments suggest that local signals also modulate GP function. We devised a genetic mouse model to study extrinsic long bone growth modulation, in which injury is specifically induced in the left hindlimb, such that the right hindlimb serves as an internal control. Remarkably, when only mesenchyme cells surrounding postnatal GPs were killed, left bone growth was nevertheless reduced. GP signaling was impaired by altered paracrine signals from the knee joint, including activation of the injury response and, in neonates, dampened IGF1 production. Importantly, only the combined prevention of both responses rescued neonatal growth. Thus, we identified signals from the knee joint that modulate bone growth and could underlie establishment of body proportions.

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