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
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.
Osteoporosis
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.
