Of the six known high affinity insulin-like growth factor binding-proteins (IGFBPs), IGFBP-4 appears to be unique in that it is the only IGFBP that functions mostly like a traditional binding protein. In this regard, none of the IGF independent effects that have been ascribed for other IGFBPs have been described for IGFBP-4. However, recent in vitro and in vivo studies, in particular the recent identification of pregnancy-associated plasma protein-A as a major IGFBP-4 protease, are consistent with the idea that IGFBP-4 is an extremely important component of IGF system in several tissues including gonads and bone. In this review, we have provided an update on IGFBP-4 research and we have summarized our current understanding of the regulation of levels and actions of IGFBP-4 and proteolytic fragments both in vitro and in vivo.
