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Review
. 2021 Dec 18;10(12):3576.
doi: 10.3390/cells10123576.

Pregnancy-Associated Plasma Protein (PAPP)-A2 in Physiology and Disease

Vicente Barrios  1   2   3 , Julie A Chowen  1   2   3   4 , Álvaro Martín-Rivada  1   2 , Santiago Guerra-Cantera  1 , Jesús Pozo  1   2   5 , Shoshana Yakar  6 , Ron G Rosenfeld  7 , Luis A Pérez-Jurado  8   9   10 , Juan Suárez  11   12 , Jesús Argente  1   2   3   4   5
Affiliations
Review

Pregnancy-Associated Plasma Protein (PAPP)-A2 in Physiology and Disease

Vicente Barrios et al. Cells. .

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.

Keywords: IGF1; IGF2; IGFBPs; PAPP-A; PAPP-A2; STC1; STC2; growth hormone axis.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Data can be provided under request.

Figures

Figure 1
Figure 1
The GH-IGF axis and its endocrine, autocrine, and paracrine actions.
Figure 2
Figure 2
The role of PAPP-A, PAPP-A2, STC1 and STC2 in the IGF system.
Figure 3
Figure 3
PAPPA2 gene mutations described to date. Schematic representation of the genomic structure of the PAPPA2 gene on chromosome band 1q24, the encoded mRNA and the protein with its relevant functional domains. The stars indicate the location in the exons, mRNA and protein where the subjects’ mutations are found.
Figure 4
Figure 4
PAPP-A2 null patient has narrower dentin tubules at seen at magnifications of 60× and 100×. Both odontoblasts and amyloblasts have impaired function in the patient.
Figure 5
Figure 5
Analysis of plasma concentrations of total IGF1 (A), body weight (BW) before and after 12 h-fasting (B), and caloric intake relative to BW after 3 week-feeding of a standard (STD: 2.9 kcal/g) or a high carbohydrate (HCHD: 3.85 kcal/g) diet (C) in constitutive Pappa2 KO mice of both sexes at 8 months old. Data are represented as mean ± S.E.M. (n = 7–8/group). Tukey-corrected tests: */*** p < 0.05/0.001 versus respective Pappa2wt/wt mice; ## p < 0.01 versus mice before 12 h-fasting.
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