Further Development 19.11: Growth Hormone and Estrogen Receptors

Development of the Tetrapod Limb

One of the major hormones involved in growth control is, of course, growth hormone (GH). Growth hormone usually acts indirectly, instructing the liver to synthesize insulin-like growth factor-I (IGF-I). IGF-I stimulates the production and division of the cartilage cells. In most giants, there is an increase in the production of growth hormone. Among African Pygmies, a people noted for short stature, there appears to be a severe reduction in the number of growth hormone receptors, resulting in a reduction of liver IGF-I and small limbs (Bozzola et al. 2009). Similarly, certain small breeds of dogs (such as Pomeranians and toy poodles) are characterized by a reduced-function allele of Igf1, whereas large breeds (such as Newfoundlands and St. Bernards) are characterized by different allele of this gene (Sutter et al. 2007; Parker et al. 2010).

The pubertal growth spurt and subsequent cessation of growth are induced by increased growth hormone production regulated by the gonadal steroid hormones (Kaplan and Grumbach 1990). Estrogen appears to be important for bone growth in both men and women. Relatively low levels of estrogen stimulate skeletal growth in men and women, whereas the higher levels that occur at the end of puberty induce apoptosis in the hypertrophic chondrocytes and stimulate the invasion of bone-forming osteoblasts into the growth plate. There have been several documented cases of men who do not produce estrogen (Smith 1994; Juul 2001). These men continue to grow even in adulthood and may approach 7 feet in height. Their epiphyseal growth plates do not mature and thus remain full of dividing chondroblasts. In most cases, this deficiency is due to a loss-of-function mutation in the gene encoding aromatase, the enzyme that converts testosterone into estrogen; in such instances, therapy with estrogens is able to stop the excessive growth.

Estrogen receptors are found in the cells that regulate growth hormone production, as well as in all the cells of the human growth plate. Thus, the effects of estrogen on growth may involve both the regulation of growth hormone and more local effects on the growth plate itself (Juul 2001; Karimian and Sävendahl 2011). Both growth hormone and estrogen antagonists (such as aromatase) can increase final height of young boys and girls, but there are often severe side-effects (Karimian and Sävendahl 2011; Mauras 2011). It is even possible that estrogen ensures that all the growth plates of the body close at about the same time (Nilsson and Baron 2004).

Parathyroid hormone-related peptide and Indian hedgehog

The growth plate is a rapidly changing population of cells. In young rats, for instance, there are about 40 cells in a column of chondrocytes. During peak growth, about eight cells per day die and are replaced by bone, and another eight chondrocytes replace them (Wilsman et al. 1996). The length of these proliferating chondrocyte columns is controlled largely by parathyroid hormone-related peptide (PTHrP) and Indian hedgehog (Ihh). Ihh maintains chondrocyte cell division directly (by activating cyclin D1 synthesis) and prevents the chondrocytes’ immediate hypertrophy. Ihh is made by the cartilage at the “bottom” of the column as the chondrocytes begin to hypertrophy. This Ihh diffuses “upward,” stimulating cell division and increasing the number of new chondrocytes in the column. PTHrP, which is stimulated by Ihh, prevents premature hypertrophic differentiation in the young chondrocytes at the base of the growth plate. As the chondrocytes leave the influence of PTHrP, they begin to hypertrophy, die, and are replaced by bone. In this way, Ihh and PTHrP regulate the length of the chondrocyte columns (Figure 1; Vortkamp et al. 1996; Kobayashi et al. 2005). In humans, mild loss-of-function mutations in the protein encoding PTHrP result in short stature and short fingers (Provot and Schipiani 2005).

Figure 1  Model for endochondral ossification in the limb. (A)In situ hybridization in the limb of a 14.5-day mouse embryo showscollagen-2 mRNA (green) in the proliferative growth plate cartilageand Gdf5 mRNA (red) in the region destined to become a joint.Nuclei are stained blue. (B) Regulation of cartilage cell proliferationby PTHrP and Indian hedgehog. (1) PTHrP acts on receptorson proliferating chondrocytes to keep them dividing and therebydelays the production of Ihh. (2) When the source of PTHrP productionbecomes sufficiently far away, then Ihh is synthesized. Indianhedgehog acts on its receptor on chondrocytes to increase the rateof proliferation and (3) to stimulate the production of PTHrP at theends of bones. (4) Ihh also acts on the perichondrial cells envelopingthe cartilage to convert them into the osteoblasts of the bonecollar. (A courtesy of Dr. P. Tylzanowski; B after Kronenberg 2003.)

Literature Cited

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