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Regulation and modulation of growth

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Title Regulation and modulation of growth
Period 01 / 2006 - 05 / 2011
Status Completed
Dissertation Yes
Research number OND1317972
Data Supplier ZONMW

Abstract

Growth disorders are a major concern for patients and their parents, and represent a clinical challenge to health care professionals at all levels. Although genetic aetiologies for isolated growth hormone (GH) deficiency and combined pituitary hormone deficiencies have been elucidated over the last 20 years, our understanding of growth failure in the presence of normal GH secretion remains primitive, which hampers the development of new treatment strategies for children with short stature. Final height gain in currently available therapeutic regimens is restricted by puberty and the associated acceleration of growth plate fusion. An intact GH-Insulin-like growth factor I (IGF-I) system is of pivotal importance for normal growth, but estrogen has a Growth is a multifactorial process involving a multitude of genetic, hormonal, nutritional and other environmental determinants (1). A disturbance of longitudinal growth, particularly short stature, is a frequent reason for medical consultation. Although short stature in childhood, adolescence and adulthood does not necessarily lead to serious clinical problems, it is associated with psychosocial, educational and professional drawbacks and disabilities (2). Growth retardation can be caused by a primary growth disorder (bone or skeletal defects), secondary growth disorder (other causes) or idiopathic. Despite a thorough clinical and laboratory assessment according to the CBO consensus (1998), the aetiology can be identified in only a minority of patients, of which a subgroup is eligible for causal treatment (e.g. hypothyroidism) (3). In other conditions, the mainstay pharmacological option is GH therapy, which has a positive effect on growth velocity and final height, but has its drawbacks. While generally children with GH deficiency benefit from GH treatment, the results in terms of catch-up growth and final height are variable and often disappointing in other growth disorders (4). One of the reasons is that GH treatment does not only increase growth velocity, but also advances skeletal maturation, which limits height gain, as premature epiphyseal fusion results in a complete arrest in longitudinal growth (5). Presently, GH has not been approved for the treatment of children with idiopathic short stature (ISS) in European countries. A major proportion of growth is dependent upon an intact GH-IGF-I axis (6). Clinical observations have rendered compelling evidence that other hormonal pathways, especially sex steroid signalling, play an important role in the regulation of pubertal growth, bone maturation and epiphyseal plate fusion (7,8). These observations strongly imply that both in boys and girls estrogen is a main determinant for puberty-associated phenomena such as the growth spurt and growth plate fusion at the This project proposal aims at increasing the understanding of the roles of GH, IGF-I and estrogen, and particularly their interaction, in growth plate biology, including proliferation, maturation and fusion. The main goals are: One of the specific innovative elements that will be exploited in this project is the use of a new human model for chondrocyte proliferation and differentiation in the growth plate. Previously, these processes have been studied using animal models, but the species differences between animals and humans limit their usefulness. Normal human growth plate tissue is not easily accessible for research purposes. In order to be able to study the molecular mechanisms underlying human growth regulation, a model is essential. In the recently developed MSC model, human multipotent mesenchymal stem cells are harvested from foetal bone marrow. These cells have the capacity to differentiate from resting cells into mature chondrocytes, providing a unique opportunity to study the consecutive steps along the chondrogenic process from the earliest stages. New molecular techniques such as microarray for gene expression profiling in human growth plates, RNA interference and genetic manipulation by viral induction will be applied. Genetic manipulation has not been conducted before in a model representative for the human growth plate. By these techniques we can mimic disorders in the GH-IGF-I axis as have been described in the last decennium, such as defects of the GH receptor (GHR), STAT5B, IGF-I and the IGF-I receptor (IGF1R), as well as known disorders of estrogen production and action, such as defects of the estrogen receptor alpha (ERalpha) and of aromatase. This will lead to a better understanding of the regulatory networks involved in growth regulation and is expected to render new insights into the pathophysiology of growth disorders. Plan van aanpak: theoretische onderbouwing Longitudinal growth is controlled by the activity of chondrocytes in the growth plate, a narrow cartilaginous structure entrapped between the epiphyseal and metaphyseal parts of long bones. Actual bone elongation is the result of a process entitled enchondral ossification, in which growth plate chondrocytes subsequentially undergo proliferation, hypertrophic differentiation and programmed cell death, and are finally replaced by bone (19). The main endocrine modulator of this growth process is GH. It has a distinct secretion pattern with high levels being secreted during infancy, followed by a decrease until the onset of puberty, during which levels rise again. Puberty is associated with a pulsatile secretion of hypothalamic GnRH, resulting in a pulsatile secretion of luteinizing hormone (LH) (and follicle-stimulating hormone, FSH)) from the pituitary, which leads to an increase in sex steroid expression. These steroids, estrogen in particular, lead to a rise in GH and IGF-I levels. Estrogen, the second important modulator of growth, has a biphasic effect on pubertal growth regulation in both boys and girls. At the beginning of puberty, the rising level of estrogen initiates the growth spurt, whereas at the end of it, a high level induces growth plate fusion resulting in a complete arrest of longitudinal growth (20). The molecular mechanisms at the level of the growth plate underlying the effects of GH, IGF-I and estrogen on growth (mainly caused by chondrocyte proliferation) and maturation (associated with the switch from proliferation to hypertrophic differentiation) remain largely unknown.

Related organisations

Secretariat Department of Pediatrics (UL)
Financier ZonMw

Related people

Supervisor Prof.dr. J.M. Wit
Researcher Dr. M. Karperien
Doctoral/PhD student Dr. S.A. van Gool

Classification

D21700 Physiology
D23362 Pediatrics

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