Systemic Regulation. After birth, GH becomes an important modulator of longitudinal growth and appears to be, together with IGF-1, the central player in the hypothalamus–pituitary–growth plate axis.14 According to the original somatomedin hypothesis,32 GH stimulates hepatic production of IGF-1, which in turn promotes growth directly at the epiphyseal plate.17 GH acts on resting zone chondrocytes and is responsible for local IGF-1 production, which stimulates clonal expansion of proliferating chondrocytes in an autocrine/paracrine manner.33 Infusion of GH or IGF-1 shortens stem- and proliferating-cell cycle times in the growth plate of hypophysectomized rats and decreases the duration of the hypertrophic differentiation phase, with GH being more effective.17 According to the experimental study of Hunziker and colleagues,34 GH or IGF-1 treatment restores mean cell volume and height, but the growth rate is not normalized by either hormone.
Thyroid hormones also play a vital role in bone growth. T3 and, to a lesser extent, T4 are crucial in normal bone maturation.30,35 Childhood hypothyroidism causes growth failure; growth failure may develop insidiously, but, once established, it is severe.17 On the other hand, hyperthyroidism increases the growth rate in children but also leads to premature growth plate fusion and short stature.36,37 T3 seems to stimulate recruitment of cells from the germinal zone to the proliferating zone and facilitates differentiation of growth plate chondrocytes.38-40 Its precursor, T4, increases the number of [3H]methylthymidine-labeled chondrocyte nuclei and [35S]incorporation in Snell dwarf mice growth plates, suggesting a stimulatory role in chondrocyte proliferation and differentiation.41
Glucocorticoids suppress growth by modifying the GH/IGF-1 pathway at different levels.17 Silvestrini and colleagues42 localized the glucocorticoid receptor in rat bone cells, including chondrocytes. The glucocorticoid receptor was also localized by Abu and colleagues43 in human growth plates, especially in hypertrophic chondrocytes, suggesting direct effects of glucocorticoids on the growth plate. An excess of glucocorticoids enhances bone resorption, inhibits osteoblast activity, and reduces bone matrix production to retard growth in children.44,45 Excess glucocorticoids also induce apoptosis of osteoblasts and osteocytes in rabbit trabecular bone46 and osteoblasts in rat long bones,47 resulting in an almost complete absence of new bone formation.17 In addition, glucocorticoids induce sex hormone deficiency and alter vitamin D metabolism, leading to deleterious effects on growth and skeletal integrity.48 Excess glucocorticoids modify the GH/IGF-1 pathway at different levels, suppressing growth.17 In contrast, low levels of glucocorticoids, as in familial glucocorticoid deficiency, are associated with tall stature.49
Longitudinal bone growth is also based on sex hormones, especially during puberty.17 In rats, estrogen depletion stimulates longitudinal growth, whereas estrogen administration inhibits longitudinal growth.50-52 Nilsson and colleagues53 studied ovariectomized immature rabbits treated with either estrogen or the selective estrogen receptor modulator raloxifene and found reduced chondrocyte proliferation and growth plate height as well as accelerated growth plate senescence. Many experimental studies have concluded that estrogen can inhibit longitudinal growth in the absence of GH.51,54,55
Androgens can directly influence growth plate function and may account for some skeletal differences between males and females.56-58 Unlike estrogens, androgens stimulate longitudinal growth, as shown in several studies that assessed the effect of administering nonaromatizable androgens on longitudinal growth in boys with constitutionally delayed growth.59,60
Local Regulation. Inh, a master regulator of bone development, coordinates chondrocyte proliferation, chondrocyte differentiation, and osteoblast differentiation.31 Inh belongs to the hedgehog protein family, which plays a crucial role in embryonic patterning and development.4 The proliferative effect of Inh is likely to be direct action on chondrocytes.31 In 1996, Vortkamp and colleagues61 reported that misexpression of Inh in chicken long bones blocked chondrocyte differentiation. More recently, St-Jacques and colleagues62 studied Inh-null mutant mice and found failure of both chondrocyte differentiation and osteoblast development. Inh is now thought to coordinate endochondral ossification, regulating chondrocyte proliferation and differentiation and osteoblast differentiation and coupling chondrogenesis and osteogenesis.62,63
PTHrP acts primarily to keep proliferating chondrocytes in the proliferative pool.31 Mice that did not express PTHrP showed accelerated chondrocyte differentiation leading to dwarfism.64 On the other hand, ectopic expression of PTHrP in the growth plate inhibited chondrocyte differentiation, resulting in a smaller cartilaginous skeleton compared with wild-type mice.65 PTHrP appears to regulate the rate of programmed chondrocyte differentiation in developing endochondral bone and at the level of the growth plate.64,66-69
The family of FGFs, which are major regulators of embryonic bone development, has at least 22 members.70,71 Achondroplasia, the most common type of dwarfism, is caused by an activating mutation in FGF receptor 3 (FGFR3).72-74 FGF18 deficiency also leads to delayed ossification and decreased expression of osteogenic markers.75
Bone morphogenetic proteins (BMPs) are recognized as important regulators of growth, differentiation, and morphogenesis during embryology.76 In 2001, Minina and colleagues77 showed that normal chondrocyte proliferation requires parallel signaling of both Inh and BMPs and that BMPs can inhibit chondrocyte differentiation independently of the Inh/PTHrP pathway.
