Many signalling pathways, local and systemic, have been demonstrated to regulate longitudinal bone growth. Systemic factors include growth hormone (GH), insulin- like growth factors (IGFs), insulin, thyroid hormone, leptin, sex steroids, vitamin D, and glucocorticoids. There are also local regulators in the growth plate such as fibroblast growth factors (FGFs), and bone morphogenetic proteins (BMPs). Dysregulation of these signalling pathways may cause excessive growth and tall stature.
Growth Hormone and IGF- I
Growth hormone (GH) is a single polypeptide chain produced by the pituitary gland. Secretion is regulated by the hypothalamic peptides, growth hormone- releasing hormone (GHRH) and the inhibitory hormone somatostatin. It is also stimulated by ghrelin produced in the stomach while IGF- 1 exerts negative feedback control. Growth hormone stimulates longitudinal bone growth both via direct stimulation of the growth plate, and indirectly by stimulating the hepatic production of IGF- 1. IGF- 1 is also ubiquitously expressed in many other tissues such as fat, muscle and in the growth plate. It has systemic effects on amino acid up take, bone mineral density, muscle mass, and lipolysis. In addition, it has local effects in the growth plate under the influence of GH stimulating both proliferation and hypertrophy of chondrocytes as well as ossification by affecting the osteoblasts. In a growing individual, a GH secreting pituitary adenoma will cause accelerated growth and tall stature which is referred to as pituitary gigantism.
Sex Steroids
Sex steroids including oestrogen and testosterone are mainly produced by the gonads. Oestrogens play an important role for growth in both girls and boys. In girls, oestrogens are mainly produced in the ovaries. In boys, the main production occurs in peripheral tis sues through aromatization of androgens. Oestrogens affect growth by reducing IGF- 1 mediated negative feedback which regulates the effect of GH and its secretion. Oestrogens stimulate growth during puberty but are also the factor that finally leads to growth plate fusion at the end of puberty in both genders. Testosterone increases the effect of GH on IGF- 1 secretion. Androgen receptors are expressed in the human growth plate but any local direct effects of androgens on longitudinal bone growth have not been established.
Oestrogens act by binding two different nuclear receptors in the growth plate, oestrogen receptor (ER)α and ERβ, and a more recently discovered G protein- coupled oestrogen receptor 1 (GPER1). ERα and ERβ are both expressed throughout the different zones of the growth plate. The abundance of both receptors increases as the cells differentiate. Oestrogens stimulate osteoblasts and inhibit osteoclasts but the exact mechanisms through which they promote bone growth are not clear. Open growth plates at 28 years of age were observed in a 204 cm tall male who had an ERα inactivating mutation. Patients with aromatase deficiency exhibit similar phenotypes with a lack of pubertal growth spurt and growth plates which remain open into adulthood leading to tall stature. Patients with aromatase deficiency respond to oestrogen treatment which improves bone mineralization and closes the growth plates. Such therapy has no effect in an ERα- mutated patient suggesting that ERα has an important role for growth plate fusion in humans.
Local Regulators of Growth in the Growth Plate
One type of local regulator in the growth plate are fibroblast growth factors (FGFs) which have important roles at every stage of endochondral bone formation. Fibroblast growth factor- 1 and FGF- 3 are growth- inhibiting whereas FGF- 2 is growth promoting. Bone morphogenetic proteins (BMPs) are also present throughout the endochondral ossification process and seem to have antagonizing effects to FGFs in some of the stages. Parathyroid hormone- related peptide (PTHrP) has a stabilizing role in the growth plate by maintaining chondrocytes in a proliferative stage and also inhibiting hypertrophy. C- type natriuretic peptide (CNP) is a local positive regulator of growth. Activating mutations or overexpression of CNP can cause tall stature.
