The IGF system and bone.

All components of the IGF systems and all regulatory mechanisms known are present and active in bone tissue. Osteoblasts synthesize IGF-I and IGF-II which have mitogenic effects on bone cells. Although the relative productions of IGF-I and IGF-II by osteoblasts are different depending on different bone districts and experimental conditions, it seems now that IGF-II is, in general, more expressed than IGF-I. The synthesis of IGFs is down-regulated by many locally produced growth factors, particularly trasforming growth factor β (TGF-β) and cortisol, and this probably accounts for the osteoporotic effects of this steroid, whereas PTH is stimulatory. Similarly to other tissues, IGFs action on bone is not only limited to cell replication but also to differentiated functions, such as production of collagen and matrix apposition. Binding proteins 2-5 have been demonstrated to be present in bone, the most expressed being IGFBP-4 and -5. Unlike IGFBP-4 which has an inhibiting effect on IGF actions, IGFBP-5 has a potentiating effect, both in vivo and in vitro, probably by binding directly to sites which are independent of the IGF receptor. The involvement of IGFBP proteases has also been demonstrated in human osteoblasts which are stimulated by IGF-II and TGF-β. In a rat osteoblast cell culture that we studied, IGF-II and IGFBP-2 were the most abundant peptides of the IGF system released in cell medium, IGFBP-5 was abundantly expressed but bound to cell surface and cell matrix and IGF-I and IGFBP-3 were found at very low concentrations. All these peptides reach the maximum concentration in the first stage of maturation and gradually decrease in the following stages. Also IGFBP proteases, namely MMP-2, are important actors of the systems, being involved in the inactivation of IGFBPs in the late stages of maturation.