Abstract
The insulin-like growth factor (IGF) axis is required for the differentiation, development, and maintenance of bone tissue. Accordingly, dysregulation of this axis is associated with various skeletal pathologies including growth abnormalities and compromised bone structure. It is becoming increasingly apparent that the action of the IGF axis must be viewed holistically taking into account not just the actions of the growth factors and receptors, but also the influence of soluble high affinity IGF binding proteins (IGFBPs).There is a recognition that IGFBPs exert IGF-dependent and IGF-independent effects in bone and other tissues and that an understanding of the mechanisms of action of IGFBPs and their regulation in the pericellular environment impact critically on tissue physiology. In this respect, a group of IGFBP proteinases (which may be considered as ancillary members of the IGF axis) play a crucial role in regulating IGFBP function. In this model, cleavage of IGFBPs by specific proteinases into fragments with lower affinity for growth factor(s) regulates the partition of IGFs between IGFBPs and cell surface IGF receptors. In this review, we examine the importance of IGFBP function in bone tissue with special emphasis on the role of pregnancy associated plasma protein-A (PAPP-A). We examine the function of PAPP-A primarily as an IGFBP-4 proteinase and present evidence that PAPP-A induced cleavage of IGFBP-4 is potentially a key regulatory step in bone metabolism. We also highlight some recent findings with regard to IGFBP-2 and IGFBP-5 (also PAPP-A substrates) function in bone tissue and briefly discuss the actions of the other three IGFBPs (-1, -3, and -6) in this tissue. Although our main focus will be in bone we will allude to IGFBP activity in other cells and tissues where appropriate.
Highlights
The insulin-like growth factor (IGF) axis comprises two polypeptide growth factors (IGF1 and IGF2), two cell surface receptors [IGF1 receptor (IGF1R) and IGF2R], and six soluble high-affinity IGF-binding proteins (IGFBP-1–6)
The observation of IGFBP-4 proteolysis by fibroblast and bone cell cultures has attracted much interest as a means of regulating the activity of IGFs in bone and other tissues, and we provide a short summary of this area
In agreement with the abovementioned findings, IGFBP-2 potentiated IGF2-induced increases in ALP activity in cultures of rat tibial osteoblasts [109], and we have demonstrated the same effect of IGFBP-2 on IGF1-stimulated ALP activity in differentiating human dental pulp cells [110]
Summary
The insulin-like growth factor (IGF) axis comprises two polypeptide growth factors (IGF1 and IGF2), two cell surface receptors [IGF1 receptor (IGF1R) and IGF2R], and six soluble high-affinity IGF-binding proteins (IGFBP-1–6). Insulin-like growth factor-binding protein-4 was first identified as an inhibitory IGFBP in medium conditioned by the TE89 human osteosarcoma cell line [23] and cloned from cDNA libraries of various tissues in human and rat [24, 25] It is a 237-residue protein sharing the 3-domain structure previously described for other IGFBPs. Early studies showed that IGFBP-4 inhibited IGF2-stimulated thymidine uptake in primary cultures of human osteoblasts (hOB) [26] and in the MC3T3-E1 mouse osteoblast cell line [27] and inhibited IGF1-stimulated aminoisobutyrate uptake in bovine fibroblasts and in the rat neuronal B104 cell line [28, 29]. IGFBP-4 protease activity has been reported in human endometrial stromal cells [43] and in porcine aortaderived smooth muscle cells [44], suggesting that proteolysis of IGFBP-4 may have widespread biological significance At around this time, a landmark study identified PAPP-A as the enzyme responsible for IGF-dependent cleavage of IGFBP-4 in fibroblastconditioned medium [34]. Structure, and regulation of PAPP-A activity are discussed below
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