The zinc metalloproteinase, PAPP-A was firstly identified as one of the four placental antigens of unknown function found in high concentrations in the plasma of pregnant women (Gall and Halbert, 1972), hence the name ‘pregnancy-associated plasma protein-A’ (Lin et al., 1974). Subsequent studies found PAPP-A mRNA to be expressed in a variety of cell types and tissues unrelated to pregnancy (Overgaard et al., 1999).

Along with PAPP-A, three other (non-proteolytic) pregnancy-associated proteins were described and were named PAPP-B, -C, and -D based on positions of precipitate lines in immunodiffusion experiments. PAPP-A was shown to enhance insulin-like growth factor (IGF) action through specific cleavage of inhibitory IGF binding protein (IGFBP), primarily IGFBP-4 (Lawrence et al., 1999). Cleavage of IGFBP-4 results in loss of binding affinity for IGF, causing increased IGF bioavailability for IGF-IR-mediated proliferation, survival and migration (Conover and Oxvig, 2018).

Accumulating evidences indicate that PAPP-A is involved in the pathogenesis of placental disorders. PAPP-A is primarily secreted from the placental syncytiotrophoblasts and thought to be involved in normal implantation and placental development. Low PAPP-A reportedly increases the risk of developing preeclampsia, preterm birth, pregnancy loss, and low birth weight (Dugof et al., 2004; Krantz et al., 2004).

The ovary has a reservoir of primordial follicles that is depleted as follicles gradually and regularly leave the resting pool and initiate growth. Folliculogenesis is one of the most complicated mechanisms in animals. The follicular microenvironment is involved in regulating a critical transition in late follicular development, the selection of the dominant follicle (DF) (Fortune et al., 2004; Choi, 2019). Interestingly, PAPP-A is strongly expressed in the granulosa cells (GCs) of a healthy DF (Matsui et al., 2004). It can be postulated that PAPP-A has an important role in folliculogenesis.

On the other hands, PAPP-A is closely related to wound healing like skin as an IGFBP-4 proteolytic activity (Chen et al., 2003). And many studies proposed a link between PAPP-A and various cancers such as breast (Kuhajda and Eggleston, 1985), ovary (Tanaka et al., 2004), lung (Bulut et al., 2009), and Ewing Family Tumors (Staege et al., 2004), etc. But, multiple regulatory functions of PAPP-A are still unknown and currently being revealed in academic and diagnostic fields. So, this review will focus on what is currently known about the PAPP-A, and its physiological roles specifically in pregnancy, folliculogenesis, and various cell types.

PAPP-A facilitates the actions of the IGF family to promote placental growth and function. IGF family promotes cellular proliferation, differentiation, and metabolism and therefore takes part in the control of placental and fetal growth. PAPP-A increases the bioavailability of IGF-1 and -2, and is therefore involved in biological pathways promoting trophoblast invasion and vascularization of the placenta (Gagnon and Wilson, 2008).

There is a positive correlation between PAPP-A levels and placental weight (Pedersen et al., 1995). In addition to being associated with aneuploidy, low levels of PAPP-A have been suggested to be a marker for impaired placental formation and implantation (Ong et al., 2000). Normal PAPP-A level in first trimester showed that there was normal placental thickness in 85.1% of cases while low level of PAPP-A only in 34.4% showed thick placenta. Therefore, PAPP-A level in first trimester have more applications in predicting normal placenta (Mesdaghi-Nia et al., 2016).

Relationship between faulty placenta and adverse prenatal outcome in one hand and observations that suggest measurement of specific circulating trophoblast-derived proteins in the first trimester of pregnancy in other hand may provide a potential screening tool to identify women at increased risk of subsequent adverse pregnancy outcome. At 11-13 weeks’ gestation, low maternal serum PAPP-A levels are associated with fetal death in utero and birthweight (Kwik and Morris, 2003). In singletons, low concentration of PAPP-A in the first trimester is associated with an increased risk of small for gestational age, intrauterine demise, preterm delivery or preeclampsia (Gagnon and Wilson, 2008; Turner and Kumar, 2020). In twin gestations, the relationship between PAPP-A and perinatal outcome is not well established. The literature data are contradictory there are both outcomes similar to singletons (Laughon et al., 2009; Rosner et al., 2015).

Many studies about chromosomal abnormalities such as trisomy 21 (Down’s syndrome, DS), have demonstrated significant correlation between low maternal serum PAPP-A and placental complications in normal pregnancies. Two other serum markers, produced by the placenta, have been linked with DS, namely PAPP-A and Inhibin A. PAPP-A has been shown to be reduced in the first trimester of DS pregnancies, with its most marked reduction in the early first trimester (Bersinger, 1995).

Measurement of maternal serum PAPP-A at late in the first trimester of pregnancy in conjunction with maternal age, maternal serum hCG and fetal nuchal translucency is used to determine the risk of fetal abnormalities such as trisomy 21, with a detection rate of over 90% for a 5% false positive rate (Malone et al., 2005). Taken together, a measurement of serum PAPP-A in first trimester can help find out the risk of the baby having certain birth defects.

Ovarian folliculogenesis begins while the female is in-utero. The number of morphologically healthy oocytes in the ovaries of mammals is remarkably variable at birth, ranging approximately from 350,000 to 1,100,000 in humans (Gougeon et al., 1994) and 14,000 to 250,000 in cattle (Erickson, 1966). Peripartum, each germ cell cyst regresses to form a primordial follicle containing an oocyte and a single layer of nourishing GCs. Many germ cells are lost during this process. After mitosis completion, the germ cells enter meiosis and arrest in meiotic prophase I, forming germ cell cysts.

The ovary has two primary functions. First, the ovary produces hormones that drive the female reproductive system. Second, the ovary controls the development, selection, and release of a mature oocyte for fertilization (Cox and Takov, 2021). Sex steroids such as FSH, LH, estrogen, and progesterone, etc. play important roles in the growth and differentiation of reproductive tissues and in the maintenance of fertility. Among them, FSH promoting GCs proliferation and differentiation stimulates follicle progression from the preantral to the preovulatory stage. Gougeon (1986) reported chronology of the process of folliculogenesis in ovary. It was classified as primordial, primary, secondary, preantral, early antral, and preovulatory stages.

Folliculogenesis can be divided into two rather distinct stages: the gonadotropin-independent (preantral) around 300 days and gonadotropin-dependent (antral or Graafian) periods for 50 days, respectively. After antrum formation, the follicle becomes dependent on FSH stimulation for continued growth and development (Giudice, 2001; Kim et al., 2020). Although FSH is the primary regulator of DF development, it is now clear that growth factors (GFs) produced by the follicle itself can act by autocrine and paracrine mechanisms to modulate, either amplify or attenuate, FSH action (Erickson and Shimasaki, 2001). FSH and IGF signaling are crucial for folliculogenesis. The physiological significance is demonstrated that the IGFBP-4 is expressed in atretic, but not healthy follicles. These findings have implicated IGFBP-4 through its FSH antagonist activities in regulatory pathways that lead to follicle atresia (Erickson et al., 1992).

The gene encoding PAPP-A is expressed in ovaries, being restricted to GCs in healthy Graafian follicles. By in situ hybridization, PAPP-A mRNA was strongly localized to the membrana GCs of healthy DF but not atretic follicle (Fig. 1). Matsui et al. (2004) reported that the regulated expression of PAPP-A might plays a role in controlling survival, growth, and/or differentiation of the DF by inactivating the gonadotropin antagonist IGFBP-4. And they also revealed that FSH and oocyte-derived bone morphogenetic protein-15 (BMP-15) can have antagonistic roles in regulating PAPP-A expression.

Figure 1.PAPP-A mRNA is expressed in healthy preovulatory follicle (HF), but not in atretic follicle (AF) using in situ hybridization (top: bright field; bottom: dark field) (quoted from Matsui et al., 2004).

Recently, scientists mentioned PAPP-A as a promising therapeutic target for healthy longevity. Because reduced IGF signaling has been associated with longevity and increased health span, a reduction in PAPP-A proteolytic activity represents a novel approach to indirectly decrease the availability of bioactive IGF. Conover et al. (2010) reported that both male and female PAPP-A knockout (KO) mice on chow diet live 30-40% longer than wild-type (WT) littermates, with no secondary endocrine abnormalities such as circulating levels of growth hormone, IGF-I, glucose, and insulin. PAPP-A KO mice also live longer when fed a high fat diet starting as adults (Conover et al., 2015).

One of the most interesting roles of PAPP-A is related to wound healing. PAPP-A cleaves IGFBP-4 and -5 and appears to enhance local IGF bioavailability in response to injury (Chen et al., 2003). During wound healing, PAPP-A expression was induced in dermal granulation tissue within and adjacent to the injury. PAPP-A was present in dermis on d 2 and was increased in intensity and extent on d 8 and 14. PAPP-A expression in cells of granulation tissue colocalized with α-smooth actin staining of myofibroblasts and new blood vessels as well as with CD68 staining of macrophages and was associated with the compact, newly synthesized collagen of the healing wound (Fig. 2). These data demonstrate localized and regulated expression of PAPP-A in human skin and suggest that PAPP-A may play an important role in an integrated IGF system in wound healing and tissue remodeling in vivo (Resch et al., 2004).

Figure 2.PAPP-A, IGF-1, and IGFBP-4 immunostaining in human skin 2, 8, and 14 d post wounding. Magnification, 60. Solid arrows, epidermis; open arrows, dermis (quoted from Chen et al., 2003).

The earliest studies suggest that PAPP-A acts as an oncogene. In breast cancer, Chander et al. (2011) studied MMTV-Skp2B transgenic mice, which develop mammary tumors that are associated with increased IGFBP-4 proteolysis and increased PAPP-A expression. PAPP-A acting as a tumor suppressor gene was epigenetically silenced in breast cancer precursor lesions, and that tumors became more invasive after downregulation of PAPP-A (Loddo et al., 2014). In ovarian cancer, it was reported that downregulation of PAPP-A mRNA by using an antisense strategy decreased IGF signaling and ovarian cancer cell growth and migration in vitro, and high PAPP-A protein expression promoted metastatic ovarian cancer in vivo (Tanaka et al., 2004). Patient ovarian tumors were found to express PAPP-A, IGFBP-4 and IGF-I and -II, and these proteins were present in the ascites of women with ovarian cancer (Thomsen et al., 2015). Interestingly, PAPP-A was particularly high in ascites, with levels approximately 50-fold greater than that in serum. But there was no difference in serum PAPP-A levels between patients and controls, emphasizing the importance of PAPP-A activity locally rather than in the circulation.

In other cancers, PAPP-A was identified as a migration/invasion promoting gene in malignant pleural mesothelioma (Huang et al., 2013), and as a potential therapeutic target in Ewing sarcoma, a highly malignant pediatric cancer (Kirschner et al., 2017). The authors deemed PAPP-A to be a ‘first rate’ target for T cell receptor based immunotherapy in Ewing sarcoma.

On the other hands, the expression of PAPP-A mRNA was identified in testis. In Fig. 3, PAPP-A mRNA was strongly expressed in Sertoli cells of seminiferous tubules in adult rat testis (unpublished data). Kim et al. (2018) reported that the PAPP-A expressed in Sertoli cells may play role on regulation of development and differentiation of testicular cells through the IGF axis in neonatal porcine testis.

Figure 3.PAPP-A mRNA is expressed in seminiferous tubule using in situ hybridization (unpublished data). In the tubules, the PAPP-A mRNA is spotted in the region of Sertoli cells.

Taken together, PAPP-A is expressed in proliferating cells such as fetus in uterus, granulosa cells in follicle, dermis in wound, cancer cells, and Sertoli cells in testis. They have common characteristics of proliferation faster than normal cells with stimulating IGFs action and inhibiting IGFBPs. But we still don’t know fully the multiple functions of PAPP-A. In Fig. 4, the PAPP-A gene network shows interactions between gene/protein by expression, regulation or protein binding (unpublished data). The PAPP-A function and expression studies in livestock have not yet been conducted much. Further studies are needed to use PAPP-A as a marker for healthy longevity in animal science.

Figure 4.The prediction of molecular network of PAPP-A gene (unpublished data) using Pathwaystudio software. This software can analyze the known gene/protein interaction from the RasNet database. Each arrows shows interactions between gene/protein by expression, regulation or protein binding.

None.

Conceptualization, S.H.; investigation, J.L., J.S., E.J., D.K. and D.L.; writing-original draft preparation, E.J. and S.H.; writing-review and editing, S.H. and M-H.H.

This work was supported by a grant from the “Cooperative Research Program for Agriculture Science & Technology Development (Project No. PJ01681301)” and 2022 the RDA Fellowship Program of National Institute of Animal Science, Rural Development Administration, Republic of Korea.

Not applicable.

Not applicable.

Not applicable.

Not applicable.

No potential conflict of interest relevant to this article was reported.