THE INSULIN-LIKE GROWTH-FACTOR SYSTEM AND THE COUPLING OF FORMATION TO RESORPTION

In the adult skeleton, bone formation is regulated by an event referred to as the coupling of formation to resorption (i,e,, formation is linked to resorption), which is thought to be mediated in part by locally produced growth factors, Although human bone cells produce and human bones contain a variety of growth factors, there is sufficient evidence to document an important role for the insulin-like growth factor (IGF) system in mediating this coupling process in bone, Studies on the basic aspects of the IGF system in bone reveal that it is complex and involves a number of components which include the IGF-binding proteins (IGFBPs; mainly IGFBP-3, -4, and -5), specific extracellular IGFBP proteases, and receptors (types 1 and 2), Based on recent experimental evidence from a number of laboratories, we propose the following models of IGF action on the regulation of the coupled increase in bone formation in response to bone resorption: (1) IGF release from bone during bane resorption promotes osteoblasts to initiate cavity refilling; (2) IGF production by osteoclasts creates a population of osteoblasts in proportion to the volume of bone tissue resorbed; and (3) IGF production by stromal cells and osteoblasts predominantly regulates the extent of cavity refill, The amount of growth factor production by osteoblasts and contemporary cells of osteoblast lineage can be further controlled by both systemic and local factors which together determine the eventual level of fill-in of the resorption cavity, For example, parathyroid hormone (stimulated during calcium deficiency) causes overproduction of IGFBP-4, a binding protein that inhibits the anabolic action of IGF-II in human bone cells, which may subsequently lead to a condition in which the resorption cavity is underfilled in bone; whereas an example of local control in bone cells may be demonstrated by the acute production of IGF-II after exposure to low-amplitude-frequency electrical fields (electric fields may mediate the effects of exercise), which may promote overfilling of the resorption cavity, In conclusion, growth factors such as IGFs probably determine the extent of resorption cavity refilling, which is a key event inasmuch as underfilling results in osteoporosis and overfilling may provide a treatment for osteoporosis.