Somatic And Skeletal Growth
Growth and development are entirely under endocrine control. The key signals involved in these processes are growth hormone, thyroid hormones (Chapter 45), sex steroids (Chapters 50 and 51) and growth factors (Chapter 46). Normal growth depends on the interplay between all of these factors. In development, there are two periods of particularly rapid growth: during pregnancy and up to the 2 years immediately after birth, and around the time of puberty (Fig. 47d).
Growth hormone (GH; also known as somatotrophin) provides the main drive for growth. It is a protein released from pituitary somatotrophs under hypothalamic control (Fig. 47a) that stimulates growth in muscles, bones and connective tissue. It is essential for normal growth both before and after birth. The release of the hormone increases immediately after birth before subsiding to a low level for most of prepubertal life. There is another surge in release around the time of puberty, after which plasma concentrations again fall and then continue to decline steadily into old age. The release of the hormone varies throughout the day, with the highest levels achieved during deep sleep. The episodic appearance of growth hormone in the blood is driven by hypothalamic growth hormone-releasing hormone (GHRH), and somatostatin (SST), which inhibits growth hormone release (Chapter 44; Fig. 47a). The growth hormone receptor is linked to an intracellular enzyme, Janus kinase-2 (JAK-2) (Fig. 47b). Once activated, this enzyme binds and phosphorylates signal transduction and activation of transcription (STAT) proteins, which consequently modify gene transcription. To provide energy for growing tissues, growth hormone has an anti-insulin action in increasing plasma glucose and stimulating lipolysis (Chapter 43). However, its overall effect is anabolic, increasing protein synthesis in many tissues. Most of its effects on growth arise from the stimulation of the release of insulin-like growth factor-1 (IGF-1) (Chapter 46) into the circulation, mainly from the liver. The lifetime release of growth hormone is regulated by the genetic factors that determine body size, but full expression of its effects requires adequate supplies of metabolic fuels and the presence of the other hormones mentioned above. In the short term, it is also liberated in response to stress and exercise.
The overproduction of growth hormone in children is associated with gigantism, and underproduction with dwarfism, which is much more common. Dwarfism is currently treated with human growth hormone manufactured by genetically engineered bacteria. Growth retardation can also result from defects in the GH receptor, or problems with IGF-1 production or action. Excess growth hormone release in adults leads to disproportionate growth of the bones of the face and limb extremities, a condition known as acromegaly.
Bone growth and remodelling
The bones are a major target for growth hormone. They are composed of an organic matrix made up of the structural protein collagen, combined with glycoproteins, that forms a framework within which the mineral hydroxyapatite [Ca10(PO4)6(OH)2] is deposited. There are two main varieties of bone structure. Cortical or compact bone has a dense structure and provides most of the strength of the skeleton. It forms the outer layer of all bones and is particularly prevalent in the diaphyses (shafts) of limb bones. Trabecular or spongy bone has a more open structure than cortical bone and surrounds the marrow. Axial bones, such as the vertebrae, and the ends (epiphyses) of long bones are largely composed of trabecular matrix (Fig. 47c). In development, bones grow from the interface between the epiphysis and the diaphysis (the growth plate). The elongation of bones involves the laying down of new collagen matrix at the growth plate by rapidly dividing chondrocytes, followed by calcification (hydroxyapatite deposition) through the action of osteoblasts. When growth is complete at about 20 years of age (Fig. 47d), the growth plate itself becomes calcified and bone elongation ceases. This stage is known as epiphyseal closure, a process driven by the high levels of sex steroids present at puberty. Even in adults, bones remain dynamic structures, with substantial proportions of the skeleton (25% of trabecular bone and 3% of cortical bone) being replaced by new growth every year. Osteoblasts develop into osteocytes, cells with numerous processes that settle into spaces in the bone matrix. Osteocytes maintain the integrity of the matrix, but can also secrete acids that dissolve hydroxyapatite and thus provide free Ca2+ to the circulation when required (Chapter 48). Osteoclasts are large cells similar to macrophages (Chapter 10) that remove old bone matrix so that it can be replaced by new material. Osteoblasts, osteocytes and osteoclasts are all present in mature bone. The collective activity of these cells allows bone to be remodelled throughout life to cope with changes in skeletal stresses, and plays an essential role in the repair of broken bones. All bone cells differentiate from bone marrow stem cells. Systemic IGF-1 and locally produced IGF-1 and IGF-2 (Chapter 46) stimulate the division, differentiation and matrix-secreting activity of osteoblasts and chondrocytes (which are also involved in cartilage formation), whereas members of the transforming growth factor-β (TGFβ) family of growth factors are thought to provide the same stimuli for osteoclasts.
After the menopause women lose bone mass, leading to a weakening of the skeleton with a consequent increase in the likelihood of fractures in older women. This is due to the reduced secretion of sex steroids from the ovaries (Chapter 50), which normally suppress the production of the cytokine interleukin-6 (IL-6) in bones. High levels of IL-6 stimulate the differentiation of osteoclasts, so that bone resorption outstrips the laying down of new matrix and more bone is removed than is replaced. The condition can be successfully treated by the administration of oestrogen (hormone replacement therapy). Recent evidence suggests that bone destruction in rheumatoid arthritis may also be driven by cytokines.