IGF-binding protein-5 as a growth factor in its own right

Growth factors do not typically diffuse freely through intact tissues, but interact with a variety of soluble and insoluble macromolecules in the extracellular space. Binding of these factors to the ECM or to other extracellular proteins can alternately interfere with or potentiate their biological activity, and such interactions provide a reservoir of growth factors that may be released in a regulable manner. The insulin-like growth factors IGF-I and -II bind with high affinity to at least six distinct IGF-binding proteins (IGFBPs). In bone, IGFBP-5 tilts the metabolic balance toward bone formation. Since IGF-I exerts a similar effect, it has been thought that the effect of the binding protein is mediated by one or both of the IGFs, but now, Miyakoshi and colleagues have tested this idea by studying the effects of IGFBPs-4 and -5 in mutant osteoblasts that produce neither of the IGFs. As anticipated, IGFBP-4 inhibits osteoblast function in wild-type but not IGF-deficient cells. Surprisingly, however, these mutant cells respond as robustly as wild-type to added IGFBP-5, promoting cell growth, alkaline phosphatase activity, and osteocalcin expression. Miyakoshi et al. discuss this finding in light of reports that osteoblasts express a receptor for IGFBP-5, which appears to be distinct from the IGF-I receptor. They conclude that IGFBP-5 is itself a growth factor that can act independently of IGF-I to regulate bone formation.