The multi-functional role of insulin-like growth factor binding proteins in bone

The insulin-like growth factor (IGF) system is an important regulator of bone formation. The IGFs (IGF-I and IGF-II) are the most abundant growth factors produced by bone, and are regulated by their six high affinity binding proteins (IGFBPs). The IGFBPs are produced by osteoblasts and are responsible for transporting the IGFs and extending their half-lives. In general, IGFBP-1, -2, -4, and -6 inhibit and IGFBP-3 and -5 stimulate osteoblast function. IGFBP-4 and -5 are the most abundant IGFBPs produced by osteoblasts, and therefore they are the primary focus of this review. IGFBP-5 is an important stimulator of bone formation and may also function independently of IGFs. IGFBP-4 inhibits osteoblast function by sequestering IGF and preventing it from binding to its receptor. This review focuses on the specific IGF-dependent and IGF-independent roles of the IGFBPs in bone formation, as well as their potential mechanisms of action. In addition, discussion of the regulation of the IGFBPs by post-translational modification (i.e., proteolysis) has been included. Studies on the regulation of production and actions of IGFBPs suggest that the IGFBP system in bone is pleiotropic and capable of serving multiple effector inputs from systemic and local sources.