Abstract
The growth hormone (GH)/insulin-like growth factor (IGF) axis plays fundamental roles during development, maturation, and aging. Members of this axis, composed of various ligands, receptors, and binding proteins, are regulated in a tissue- and time-specific manner that requires precise control that is not completely understood. Some of the most recent advances in understanding the implications of this axis in human growth are derived from the identifications of new mutations in the gene encoding the pregnancy-associated plasma protein PAPP-A2 protease that liberates IGFs from their carrier proteins in a selective manner to allow binding to the IGF receptor 1. The identification of three nonrelated families with mutations in the PAPP-A2 gene has shed light on how this protease affects human physiology. This review summarizes our understanding of the implications of PAPP-A2 in growth physiology, obtained from studies in genetically modified animal models and the PAPP-A2 deficient patients known to date.
Highlights
Longitudinal bone growth is governed by chondrocyte multiplication, hypertrophy of chondrocytes and ossification, with cartilage being replaced by mineralized bone
The N-terminal domain stabilizes the proteolytic domain that is responsible for cleavage of the IGF binding proteins (IGFBPs) and, a region with five copies of complement control protein (CCP), implicated in the binding of plasma protein-A (PAPP-A) to glycosaminoglycans (GAGs) of the cell surface, can increase insulinlike growth factor (IGF) signaling by releasing IGFs in the proximity of their receptors [31]
Analysis of Pappa2 expression has been performed in zebrafish embryos, larvae and adults, with adult tissues such as bone, muscle, eye, brain, gill, kidney, gastrointestinal tract, ovary and testis shown to have higher expression levels than other tissues [66]. These findings confirm the physiological importance of PAPP-A2 in the promotion of placental, fetal and postnatal growth, and support the hypothesis that PAPP-A2 may act as a local tissue-specific modulator of IGF1 bioavailability by cleavage of ternary complexes containing IGFBP3 or IGFBP5 and IGFALS
Summary
Longitudinal bone growth is governed by chondrocyte multiplication, hypertrophy of chondrocytes and ossification, with cartilage being replaced by mineralized bone. The N-terminal domain stabilizes the proteolytic domain that is responsible for cleavage of the IGFBPs and, a region with five copies of complement control protein (CCP), implicated in the binding of PAPP-A to glycosaminoglycans (GAGs) of the cell surface, can increase IGF signaling by releasing IGFs in the proximity of their receptors [31]. The specificity of PAPP-A2 for IGFBP3 and IGFBP5 is important since the main pool of circulating IGFs is found in ternary complexes with ALS and IGFBP3 or IGFBP5 This aspect will be discussed later in this review, considering the effects of mutations in PAPP-A2 on the peripheral IGF axis and its relationship with alterations of human growth. Further understanding concerning how changes in the circulating levels of STC2 impact on free IGF1 is necessary, since transgenic [47] or Stc knockout mice [44] do not present any alterations in circulating IGF1, suggesting that the main function of this stanniocalcin could be to regulate IGF signaling at the cellular level
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