Insulinlike growth factor biological effects

IGFs exhibit a wide range of gross physiological effects (Table 10.10), all of which are explained primarily by the ability of these growth factors to stimulate cellular growth and differentiation. Virtually all mammalian cell types display surface IGF receptors. IGFs play a major stimulatory role in promoting the cell cycle (specifically, it is the sole mitogen required to promote the G1b phase, i.e. the progression phase; various other phases of the cycle can be stimulated by additional growth factors). IGF activity can also contribute to sustaining the uncontrolled cell growth characteristic of cancer cells. Many transformed cells exhibit very high levels of IGF receptors, and growth of these cells can be inhibited in vitro by the addition of antibodies capable of blocking IGF-receptor binding.

Most of the growth-promoting effects of GH are actually mediated by IGF-I. Direct injection of IGF-I into hypophysectionized animals (animals whose pituitary, i.e. source of GH, is surgically removed) stimulates longitudinal bone growth, as well as growth of several organs/glands (e.g. kidney, spleen, thymus).

Such effects render IGFs likely therapeutic candidates in treating the various forms of dwarfism caused by a dysfunction in some element of the GH-IGF growth axis. Initial trials show that s.c. administration of recombinant human IGF-I over a 12-month period significantly increases the growth rate of Laron-type dwarfs.

IGFs also play a core role in tissue renewal and repair (e.g. wound healing) during adulthood. For example, these growth factors play a central role in bone remodelling (i.e. reabsorption and rebuilding, which helps keep bones strong and contributes to whole-body calcium homeostasis). Reabsorption of calcified bone is undertaken by osteoclasts, cells of haemopoietic origin whose formation is stimulated by IGFs. These mitogens may, therefore, influence the development of osteoporosis, a prevalent condition (especially amongst the elderly), which is characterized by brittle, uncalcified bone.

IGFs are often localized within various areas of the kidney. Direct infusion of IGF-I influences (usually enhances) renal function by a number of means, including promoting increased:

• glomerular filtration rate;

• kidney size and weight.

These responses are obviously mediated by multiple effects on the growth and activity of several renal cell types, suggesting that IGFs play a physiological role in regulating renal function. Not surprisingly, IGF-I is currently being assessed as a potential therapeutic agent in the treatment of various forms of kidney disease.

IGF-I is widely expressed in the central nervous system. IGF-II is also present, being produced mainly by tissues at vascular interfaces with the brain. Both growth factors, along with insulin, play a number of important roles in the nervous system. They stimulate the growth and development of various neuronal populations and promote neurotrophic effects (discussed later) and may, therefore, be of potential use in the treatment of various neurodegenerative diseases.

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