Insulin-like growth factor binding proteins in bone cell regulation.

Recent studies emphasize that 1) IGFs are important local regulators of bone formation and 2) IGFBPs are important regulators of the biological actions of IGFs in bone. The importance of IGFs is shown by the finding that 40-50% of basal bone cell proliferation could be blocked by inhibiting the actions of IGFs produced endogenously by bone cells in serum free culture. In addition, IGFs are the most abundant growth factors stored in bone and are produced by bone cells. Recent studies suggest that IGFs are fixed in bone by means of IGFBP-5 which binds with high affinity to both hydroxyapatite and IGFs. Upon release from this storage depot, IGFs and IGFBP-5 are thought to act in the coupling of bone formation to bone resorption in a delayed paracrine manner (i.e. previously fixed IGF+IGFBP-5 complex is released in a bioactive form during bone resorption to stimulate new bone formation). In addition to IGFBP-5, human bone cells in culture have also been shown to produce other IGFBPs, some of which modulate IGF actions in either positive or negative manner. In addition, recent studies also demonstrate that local and systemic effectors of bone formation may regulate the actions of acutely synthesized IGFs (autocrine/paracrine actions) in bone cell microenvironment in a tissue specific manner by modulating the type and amount of IGFBPs produced by bone cells at a local site of bone.