Transforming Growth Factor-β Regulation of the Insulin-Like Growth Factor Binding Protein-4 Protease System in Cultured Human Osteoblasts

Disruption of insulin-like growth factor-II imprinting during embryonic development rescues the dwarf phenotype of mice null for pregnancy-associated plasma protein-A

“…Importantly, there is a striking association of IgfII and Igfbp4 gene expression (Cerro et al 1993, Schuller et al 1993, thereby allowing establishment of an IGF-II/IGFBP-4 reservoir that could be rapidly accessed by regulated increases in PAPP-A expression. Besides the proposed roles in embryological development, the PAPP-A/IGFBP-4/IGF system may be involved in post-natal bone formation as well, since PAPP-A and IGFBP-4 are highly expressed by osteoblasts and have been shown to regulate IGF action in these cells in vitro (Wang et al 1995, van Kleffens et al 1998, Ortiz et al 2003. Furthermore, the importance of regulation of local IGF action in adult bone by PAPP-A is suggested by the finding of defective fracture repair in PAPP-A-null mice (Miller et al 2004).…”

“…One of these proteases was identified as pregnancy-associated plasma protein-A (PAPP-A) (Lawrence et al 1999). PAPP-A has been shown to cleave inhibitory IGFBP-4 and consequently increase the IGF available for receptor activation in various cell systems in vitro (Conover et al 1995, Byun et al 2001, Ortiz et al 2003. In vivo, intact IGFBP-4 is postulated to form a local reservoir of IGFs that can be made available at critical times through regulated expression of PAPP-A and its associated proteolytic activity (Pintar et al 1998).…”

Pregnancy associated plasma protein-A is necessary for expeditious fracture healing in mice

“…PAPP-A is expressed by a variety of cells in culture, including osteoblasts, fibroblasts, and vascular smooth muscle cells , Bayes-Genis et al 2001, Ortiz et al 2003 and in periosteal explants (AuwYang et al 2003). In vitro studies have shown that PAPP-A enhances IGF action through cleavage of IGFBP-4, which markedly diminishes the affinity of IGFBP-4 for IGFs , Byun et al 2001, Ortiz et al 2003. PAPP-A is thought to play a similar role in vivo, to increase the availability of free IGF at the local tissue level for enhanced receptor activation during critical periods such as in response to injury.…”

Pregnancy‐associated plasma protein‐A (PAPP‐A) expression and insulin‐like growth factor binding protein‐4 protease activity in normal and malignant ovarian surface epithelial cells

“…Expression of this IGFBP-4 protease is consistent with the role of PAPP-A as a positive regulator of IGF-mediated signaling and growth. 8,9,40,41 In this role, PAPP-A cleaves IGFBP-4 and reduces its affinity for IGFs, effectively increasing local IGF bioavailability. Similar to the observation of increased PAPP-A expression in healing human skin 42 and during vascular repair, 14,15 this could be a mechanism by which PAPP-A induces the proliferation of OSE cells after ovulation and subsequent repair of the ovulation-associated wound.…”

“…6 By neutralizing the IGF-sequestering activity of IGFBP-4 by proteolysis to fragments with reduced affinity for IGF, activation of PAPP-A results in acute local increases in the levels of IGF available for interaction with IGF receptors in vitro. [7][8][9] Beyond its role in pregnancy, PAPP-A is expressed by osteoblasts 6,7 and human granulosa cells 10,11 and plays an important role in regulating IGF bioavailability in developing ovarian follicles. 12,13 In addition, PAPP-A activation is implicated in injury-repair responses in the vasculature through local increases in bioavailable IGF.…”