IGFBPs control the distribution, function and activity of IGFs in various cell tissues and body fluids. IGFBP-4 is the major IGFBP produced by osteoblasts, and is found in the epidermis, ovarian follicles, and other tissues. IGFBP-4 inhibits the activity of IGF-I and IGF-II by binding in a manner that results in the formation of complexes with reduced ability to signal through cell surface IGF receptors. IGFBP-4 can inhibit the growth of chick pelvis cartilage and HT29 colon adenocarcinoma cells by blocking the mitogenic actions of IGFs, and has also been shown to reduce colony formation by colorectal cancer cells via an IGF-independent pathway. The biological effects of IGFBP-4 can be regulated by Pregnancy Associated Plasma Protein A (PAPP-A), which reduces IGFBP-4/IGF binding affinity by proteolytically cleaving IGFBP-4. The modulation of IGFBP-4 activity by PAPP-A is an important component in the regulation of ovarian folliculogenesis and in the growth inhibition of responding ovarian cancer cells.