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BOR - Papers in Press, published online ahead of print July 30, 2004.
Biol Reprod 2004, 10.1095/biolreprod.104.030932
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BIOLOGY OF REPRODUCTION 71, 1779–1784 (2004)
DOI: 10.1095/biolreprod.104.030932
© 2004 by the Society for the Study of Reproduction, Inc.

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Parathyroid Hormone-Related Protein in Preeclampsia: A Linkage Between Maternal and Fetal Failures

Emanuela Maioli1, Vittoria Fortino, and Adriana Pacini

Department of Physiology, Section of Immunoendocrinology and Reproductive Physiology, University of Siena, 8-53100 Siena, Italy


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PTHrP AND FETAL DEVELOPMENT
 PTHrP IN PREGNANCIES COMPLICATED...
 PTHrP INVOLVEMENT IN THE...
 PTHrP AND THE CYTOKINE...
 CONCLUSION
 REFERENCES
 
Preeclampsia is a disorder associated with pregnancy that affects both the mother and the fetus. Typical features of the disease are maternal hypertension, proteinuria, and edema as well as fetal growth retardation. Although the etiological details are still being debated, a consensus exists that the starting point is deficient placentation in the first half of pregnancy. The crucial early steps are reduced trophoblast invasiveness and enhanced apoptotic death. In the present review, we demonstrate that parathyroid hormone-related protein is involved not only in the maternal and fetal failures but also in the etiological aspects of the disease. We hypothesize that reduced local production of the peptide is a major causative event.

apoptosis, cytokines, placenta, pregnancy, trophoblast


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PTHrP AND FETAL DEVELOPMENT
 PTHrP IN PREGNANCIES COMPLICATED...
 PTHrP INVOLVEMENT IN THE...
 PTHrP AND THE CYTOKINE...
 CONCLUSION
 REFERENCES
 
Parathyroid hormone-related protein (PTHrP) was discovered in 1987 as a tumor-derived factor that causes humoral hypercalcemia of malignancy; like parathyroid hormone (PTH), it can bind to the PTH/PTHrP receptor (PTHR1) in bone and kidney [1]. More recently, it has been established that the protein is ubiquitously expressed in most fetal and adult tissues and that it also plays a role in normal life [2].

The biological importance of PTHrP is its ability to control the growth, death, and secretory behavior of almost every target cell. The protein's versatility is based on complex and complete signaling (endocrine, paracrine, autocrine, and intracrine activity) [2] combined with a family of related fragments arising from alternative splicing of the PTHrP gene and alternative posttranslational cleavage sites. In fact, alternative splicing of the human PTHrP gene, consisting of nine exons, leads to the production of three different mRNAs encoding three proteins of 139, 141, or 173 amino acids, each with distinct C-terminals. In addition, each PTHrP chain undergoes cotranslational cleavages, which give rise to at least three bioactive peptides. Indeed, the PTHrP family comprises mature N-terminal, midregion, and C-terminal secretory forms, each having its own physiological function and, probably, its own receptor on the cell surface [3]. (No distinction has been made through the present text among different PTHrP isoforms and fragments, except when clearly specified.)

The fetal-placental unit is one of the main nontumor sources of PTHrP. Indeed, PTHrP is abundantly expressed in fetal and gestational tissues during normal pregnancy. In addition to the fetal parathyroid glands, sites of PTHrP production are the myometrium, the amnion, the choriodecidua, the reflected amnion, and the placenta. Expression of PTHrP is more abundant in the amnion than in other intrauterine tissues; production of the peptide is so high in this location that amniotic fluid (AF) has 10-fold the PTHrP concentrations of either maternal or fetal plasma [4]. However, fetal plasma has a higher PTHrP concentration than maternal blood, which is consistent with the notion that PTHrP is the fetal calciotropic hormone.

In each tissue location, the peptide seems to exert peculiar effects. In the myometrium, PTHrP is produced in response to the mechanical stretch accompanying uterine occupancy in pregnancy [5]. In the uterus, the protein regulates blood flow and decreases resting myometral tone, preventing spontaneous and oxytocin-induced uterine contractions [6]. It is generally held that PTHrP may play a role in maintaining uterine quiescence until term. At this time, the levels suddenly fall, allowing myometral contractile activity to increase unopposed by PTHrP [7].

Because PTHrP is decreased in AF following rupture of membranes [8], it might exert a permissive action in the mechanisms of parturition, and a role of PTHrP in the onset of labor has been suspected. The hypothesis that the fall of PTHrP could be the timely event initiating labor is particularly intriguing and worth deeper examination. However, no general consensus exists regarding whether and how PTHrP levels are changed in term and in preterm labor; discordant results have been reported. For example, Curtis et al. [9] found no changes in PTHrP mRNA and protein in amnion and choriodecidua in association with labor or rupture of fetal membranes.

The relative contribution of uterus, placenta, and membranes to PTHrP levels in AF is difficult to establish, but most PTHrP probably derives from fetal membranes, with a minimal contribution by myometrium. On the contrary, PTHrP in AF likely affects, through a paracrine action, both the uterine musculature and the placenta/membranes [8].

The best-known function of PTHrP in fetal membranes is the control of placental calcium transport [10, 11] and placental vascular tone [12]. However, increasing evidence indicates that the role of PTHrP extends beyond the local control of placental functions; indeed, the peptide's pleiotropic effects project out of the fetal membranes toward both the maternal and the fetal sides.

In the present review, we examine both old and new knowledge, and we repropose PTHrP as one of the causative factors of preeclampsia: A PTHrP deficiency could account for most of the maternal and fetal failures that are characteristic of this disease.


   PTHrP AND FETAL DEVELOPMENT
TOP
 ABSTRACT
 INTRODUCTION
 PTHrP AND FETAL DEVELOPMENT
PTHrP IN PREGNANCIES COMPLICATED...
 PTHrP INVOLVEMENT IN THE...
 PTHrP AND THE CYTOKINE...
 CONCLUSION
 REFERENCES
 
The role of PTHrP as a developmental factor is well documented [13]. The best demonstration comes from gene-deletion studies showing that both PTHrP and its receptor are essential for fetal development. Mice that are deficient in PTHrP have a reduced maternal-fetal calcium gradient and die at birth because of premature cartilage mineralization, which impairs the mechanisms of breathing [14]. Similarly, mice with deletion of the PTHR1 gene are growth-restricted and die at midgestation [15]. In humans, an inactivating mutation of the PTHR1 (in the rare Blomstrand chondrodysplasia) leads to death before birth [16].

Fetal membrane-derived and AF PTHrP may contribute to fetal development by paracrine regulation of cell growth and differentiation in several fetal tissues, such as lung, gut, and skin [4]. Indeed, PTHrP concentrations in AF peak during late pregnancy, concomitant with the rapid fetal growth and increased calcium demand that are typical of the third trimester [17].

In addition, a very recent report suggests that enhanced PTHrP levels restore fetal growth in the uterus of growth-restricted, spontaneously hypertensive rats, presumably by improving placental growth and function [18].

These preliminary remarks suggest that any pathological condition causing inadequate PTHrP expression in the fetal membranes will inevitably result in impaired fetal growth and development. As discussed in the next section, this is one of the events occurring in pregnancy complicated by intrauterine growth restriction (IUGR), whether associated or not associated with preeclampsia.


   PTHrP IN PREGNANCIES COMPLICATED BY IUGR AND PREECLAMPSIA
TOP
 ABSTRACT
 INTRODUCTION
 PTHrP AND FETAL DEVELOPMENT
 PTHrP IN PREGNANCIES COMPLICATED...
PTHrP INVOLVEMENT IN THE...
 PTHrP AND THE CYTOKINE...
 CONCLUSION
 REFERENCES
 
Normal pregnancy is associated with anatomical and functional changes of the cardiovascular system, which accommodates to the greater total blood volume by increasing the heart rate and cardiac output. Hemodynamic adaptation develops early, with generalized vasodilatation and a drop in peripheral vascular resistance. This adaptive response has two purposes: to enhance peripheral blood flow, and to prevent an increase of blood pressure. In pregnancies that are complicated by preeclampsia, hemodynamic and vascular adaptation is disturbed, and abnormal vascular responses are evident in the maternal systemic circulation.

The PTHrP appears to play several roles in the cardiovascular system: It lowers blood pressure by inhibiting long-lasting voltage-dependent calcium channels in smooth muscle cells, and it has an inotropic action by increasing transient voltage-dependent calcium currents in ventricular myocytes [19]. Therefore, PTHrP increases basal contractility of the ventricles through a double action: T-type calcium channel activation, and coronary vessel relaxation. Additionally, PTHrP exerts chronotropic effects by directly influencing the pacemaker activity of cells in the sinus node [20].

Moreover, the strong induction of PTHrP by vasoconstrictors [21, 22] and its vasorelaxant properties make it a dynamic compliance factor to accommodate flow in response to contractile stimuli. Indeed, the inhibition of PTHrP induction by angiotensin II in aortic smooth muscle cells is associated with severe hypertension in a rat model [23].

Although the full-length molecule is relatively large, PTHrP is a polyhormone that is processed into separate circulating fragments. It is generally held that small, bioactive fragments, released by fetal membranes, pass into the maternal circulation, where the N-terminal peptides especially may have a role in maternal blood pressure regulation because of their vasorelaxant properties. Whereas plasma levels of the peptide increase during normal pregnancy [24, 25], inadequate PTHrP production has consistently been observed in pregnancies that are complicated by IUGR, which is often associated with preeclampsia [26]. Preeclampsia is a disorder associated with pregnancy that consists of hypertension, proteinuria, and edema. However, the pathophysiology of preeclampsia involves much more than increased blood pressure and altered renal function. In fact, necrosis and hemorrhage are recurrent in many organs and are secondary to profoundly reduced perfusion. Reduced blood flow is caused, at least in part, by increased sensitivity of the vasculature to pressor agents, such as endothelin and angiotensin II [27], but not to increased circulating concentrations of known vasoactive molecules [28 and references therein].

Although Curtis et al. [9] did not find altered PTHrP expression in fetal membranes from preeclamptic women, the decrease in circulating levels of PTHrP in women with preeclampsia has been documented [29]. In this regard, it might be worthwhile to investigate more preeclamptic placentas and fetal membranes in terms of PTHrP expression, because no other sources of PTHrP have been ever suspected in pregnancy in addition to fetus, fetal membranes, and uterine tissues. The inadequate local PTHrP production likely is a pathophysiological mechanism of preeclampsia, because the lack of increased plasma PTHrP could tilt the maternal balance between relaxant and vasoconstrictor stimuli toward a prevalence of the latter. Although the PTHrP levels in pregnancy are not as high as in humoral hypercalcemia of malignancy, they likely do relax maternal vessels by an endocrine mechanism. Indeed, PTHrP is threefold more potent than PTH in inhibiting smooth muscle contraction, and infusion of synthetic PTHrP decreases blood pressure in a dose-dependent manner from 0.3 to 30 µg/kg. Additionally, it produces a decrease of as much as 50 mm Hg at 10 µg/kg [30].

Indirect signs of inadequate PTHrP production in preeclampsia could also be recognized in the documented alterations of calcium metabolism, such as a low urinary excretion and decreased plasma vitamin D levels [29]. Disturbed calcium homeostasis in preeclampsia is thought to contribute to the development of hypertension [31], and indeed, some clinical trials have suggested that calcium supplementation during pregnancy may prevent hypertension and preterm labor [32]. However, discordant results have been reported [33]; thus, the question remains under debate. Following the hypothesis that the lower calcium levels in women with preeclampsia are the consequence of inadequate PTHrP production and endocrine activity, calcium supplementation could, paradoxically, even increase blood pressure by suppressing PTH release by parathyroid glands.

Endothelial cell damage is a characteristic feature of preeclampsia. Because maternal endothelial disorders in preeclampsia resemble those of atherosclerosis, a common pathophysiology has been suggested [34]. In this regard, Ishikawa [35] demonstrated that PTHrP protects against atherosclerosis by inhibiting formation of neointima and stenosis in experimental atherosclerotic lesions. Although the endothelial damage in preeclampsia is thought to result from abnormal placental implantation, with reduced perfusion and ischemia (see below) as consequences, the lower circulating levels of PTHrP could be an additional risk factor.


   PTHrP INVOLVEMENT IN THE ETIOLOGY OF PREECLAMPSIA
TOP
 ABSTRACT
 INTRODUCTION
 PTHrP AND FETAL DEVELOPMENT
 PTHrP IN PREGNANCIES COMPLICATED...
 PTHrP INVOLVEMENT IN THE...
PTHrP AND THE CYTOKINE...
 CONCLUSION
 REFERENCES
 
In normal pregnancy, a subpopulation of placental cytotrophoblast cells undergoes a differentiation program consisting of invasion of the uterus and its vasculature and remodeling of the spiral arteries of the decidua and myometrium into dilated, low-resistance vessels. Preeclampsia is characterized by impaired trophoblast invasion of the spiral arteries, which remain narrow and reactive to vasoactive stimuli. This leads to uteroplacental hypoperfusion and, thus, relatively hypoxic trophoblast tissue. This first step promotes exaggerated oxidative stress in the placenta, which further attenuates the trophoblast invasion and affects vascular reactivity, blood flow, and oxygen as well as nutrient delivery to the fetus [36]. Thus, preeclampsia may be associated with intrauterine growth retardation.

On the maternal side, oxidative stress of the placenta is considered to be a key intermediate step, causing shedding of apoptotic and/or necrotic fragments into the maternal circulation. This leads to a decompensated, inflammatory response, which is manifested in the characteristic endothelial dysfunction [37]. It is generally held that preeclampsia originates from deficient placentation during the first half of pregnancy, but the causes of the initial impaired trophoblast invasiveness and the subsequent enhanced apoptosis are largely unknown. The process clearly is very complex and probably is not the result of a single cause, but PTHrP does appear to be involved in both etiological aspects of the disease, as detailed below.

PTHrP and Trophoblast Invasiveness

As mentioned previously, normal placentation requires controlled invasion of trophoblast into the maternal uterine wall, with secretion of specific proteolytic enzymes to degrade basement membranes and extracellular matrix, such as the matrix metalloproteinases (MMPs). Consistently, trophoblast gelatinolytic enzymes (particularly MMP-1, MMP-2, and MMP-9) are defective in preeclampsia [38, 39].

One of the documented pleiotropic effects of PTHrP is the stimulation of MMP expression and the release in several cell types (e.g., MMP-2, MMP-3, and MMP-9 in growth plate chondrocytes; MMP-13 in bone; and MMP-2 in skin fibroblasts) [40–42]. Although a link between inadequate PTHrP production and decreased trophoblast gelatinolytic activity has yet to be directly demonstrated, it is tempting to speculate that a cause-effect relationship also exists in this tissue. In the meantime, a role of inadequate local production of PTHrP in the reduced trophoblast invasiveness can be proposed.

PTHrP and Trophoblast Apoptosis

The program of development and differentiation of trophoblast, as well as of other tissues of the body, depends on a balance between cell proliferation and cell death. Apoptosis is a normal component of this process, which can be triggered by two main signaling pathways: the first is mediated by the interaction of membrane receptors and ligands, such as Fas ligand and tumor necrosis factor (TNF) {alpha}, and the second is triggered by exogenous stimuli that transmit the death signal through mitochondria.

Among the exogenous stimuli, hypoxia induces apoptosis in a number of cell systems. Recent studies have demonstrated that hypoxia also enhances apoptosis in cultured human trophoblast cells by modulating p53 expression and by altering the ratio of the proapoptotic Bax protein versus the antiapoptotic Bcl-2 protein [36, 43]. These findings are consistent with the higher degree of apoptosis in placentas from pregnancies complicated by IUGR and preeclampsia than in those from normal pregnancies [44].

The crucial role of PTHrP in the apoptotic process has recently been demonstrated in various cell types. The PTHrP could control the apoptotic process by three main mechanisms. The first is based on nuclear localization of the peptide (intracrine activity), resulting in direct inhibition of apoptosis induced, for example, by serum deprivation. Indeed, PTHrP behaves as a survival factor in a number of normal and cancer cells, such as chondrocytes [45], coronary endothelial cells [22], vascular smooth muscle cells [46], and MCF-7 breast cancer cells [47].

The PTHrP could also rescue cells from apoptosis by a second, indirect mechanism that consists of transactivation of the growth factor tyrosine kinase receptors (TKRs), mediated by the membrane PTHR1 (autocrine/paracrine activity). Growth factor-independent transactivation of TKRs has been reported for several G protein-coupled receptors (GPCRs) [48 and references therein], with the best-described GPCR being the receptor for angiotensin II [49]. Because PTHR1, to our knowledge the only PTHrP receptor cloned to date, is a classical type II GPCR [50], no theoretical reason exists why it should not exhibit such a property, even though this has yet to be demonstrated. In this regard, Crocker et al. [51] recently reported that an exogenous N-terminal PTHrP fragment (1–34) acts as a survival factor against cytotrophoblast apoptosis induced by transforming growth factor {alpha} and interferon-{gamma}. Although that study did not focus on PTHrP signaling, it suggests the possibility of PTHR1-mediated TKR transactivation.

Apoptosis can also be prevented by growth factors, such as nerve growth factor [52], insulin-like growth factor (IGF) [53], and epidermal growth factor (EGF) [54]. Indeed, EGF prevents trophoblast apoptosis induced by either TNF{alpha} [55] or hypoxia [43]. Interestingly, an older report indicates that PTH and PTHrP N-terminal peptides increase the synthesis of EGF receptors (EGFRs) in cultured human trophoblast cells, an effect mediated by protein kinase (PK) C [56]. Thus, PTHrP could counteract apoptosis via a third mechanism: by acting on EGFRs. Although isolated, this finding is supported by similar, more recent results in osteoblast-like cells, in which the increase in EGFR gene transcription by PTHrP was mediated by PKA [57]. Of note, despite the different signal transduction pathways, PTHrP evokes the same final response in the two cell types.

Collectively, these findings suggest that the decrease in trophoblast PTHrP expression and/or secretion results in impaired resistance to apoptotic signals and exaggerated cell death, further strengthening the crucial role played by PTHrP at the maternal-fetal interface.


   PTHrP AND THE CYTOKINE NETWORK
TOP
 ABSTRACT
 INTRODUCTION
 PTHrP AND FETAL DEVELOPMENT
 PTHrP IN PREGNANCIES COMPLICATED...
 PTHrP INVOLVEMENT IN THE...
 PTHrP AND THE CYTOKINE...
CONCLUSION
 REFERENCES
 
Several cytokines and growth factors modulate the expression and release of PTHrP. It has been postulated that unique cooperative loops exist between PTHrP and cytokines in every tissue expressing PTHrP [58].

Certain inflammatory cytokines are linked to PTHrP in human amnion cells: Interleukin (IL)-1ß and IL-6 increase both PTHrP mRNA and peptide, whereas IL-2 and IL-8 have no effect [59]. The participation of inflammatory cytokines in the regulation of PTHrP production could represent a link between the view of trophoblast invasion as an essentially inflammatory process and the release of a factor (PTHrP) derived from the fetal membranes, which could prevent or counteract the complications of inflammation in the mother. From this perspective, a failure of PTHrP induction by inflammatory cytokines could be seen as the early event causing complications later in pregnancy.

This idea raises the interesting question of what is the first defective event: the lack of cytokine release, or the failure of PTHrP induction? Unfortunately, this question remains unanswered.

Conversely, there is ample evidence of a link between PTHrP and growth factors, in particular IGF-1 and its binding proteins (IGFBPs). Experiments with different cell types have demonstrated that PTH and PTHrP, by their common N-terminal sequence, regulate the IGF/IGFBP axis, generally increasing free IGF-1 levels [60, 61].

Both IGF-1 and IGFBPs are abundantly expressed by cells at the maternal-fetal interface and mediate cell-to-cell communication between trophoblast and decidua. It has recently been shown that IGF-1 facilitates implantation of the embryo in the endothelium [62]. Although some controversy exists about the relationship between the IGF family members and preeclampsia, a consensus exists that they are involved in development of the disease. Both older and more recent studies have shown that IGF-I concentrations both in maternal and umbilical cord serum and in placental tissues are lower during preeclampsia than during normal pregnancy [63–66]. However, doubts remain whether the low levels of IGF-1 are a cause or a consequence of the disease. In other tissues, such as skin, IGF-1 stimulates PTHrP expression by keratinocytes [67]. On the other hand, PTH and the PTHrP N-terminal peptides have been reported to enhance IGF-1 expression in bone [68]. Until a similar, focused study is performed on fetal-maternal unit, we can do nothing but speculate that if inadequate PTHrP production is one of the primary causes of preeclampsia, then the decrease of IGF-1 levels could be one of the inevitable consequences. A sort of autocrine loop could also be recognized, in which underexpression of PTHrP lowers IGF-1 release, which in turn further decreases PTHrP synthesis (or vice versa).


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 PTHrP AND FETAL DEVELOPMENT
 PTHrP IN PREGNANCIES COMPLICATED...
 PTHrP INVOLVEMENT IN THE...
 PTHrP AND THE CYTOKINE...
 CONCLUSION
REFERENCES
 
Although preeclampsia affects 5–10% of pregnant women, the etiology of the disease remains obscure. Therefore, prevention has been hampered, and treatment and management have remained unchanged for at least 50 years.

The once-promising line of research concerning the existence of factor X, released from the placenta into the maternal blood [69], has been unsuccessful. Nevertheless, a consensus exists that the starting point is early defective placentation and impaired hemodynamic adaptation to pregnancy. The evidence and considerations reported here have led us to the conclusion that the defective placentation and the subsequent maternal and fetal failures are both triggered and sustained by inadequate local production of PTHrP (Fig. 1), not by the release of a novel humoral factor from the placenta.



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  		FIG. 1. Overview of the possible in vivo consequences of insufficient PTHrP production by placenta/fetal membranes

The possible implications of this view for diagnosis and therapeutic strategies are evident. Evaluation of PTHrP levels in the AF [8] could be used as an early diagnostic/ prognostic test, and the maternal plasma concentrations [24] could easily be monitored throughout pregnancy.

Clearly, further investigations are needed to cure affected women and their fetuses, but the identification and testing of physiological or pharmacological inductors of PTHrP could initiate a new area of research aimed at the prevention and efficacious treatment of preeclampsia.


   ACKNOWLEDGMENTS
 
The authors thank Prof. Luana Ricci Paulesu for her careful reading of the manuscript and her helpful comments.


   FOOTNOTES
 
1 Correspondence: Emanuela Maioli, Department of Physiology, Via Aldo Moro, 8-53100 Siena, Italy. FAX: 39 577 234219; maioli{at}unisi.it Back

Received: 14 April 2004.

First decision: 13 May 2004.

Accepted: 7 July 2004.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 PTHrP AND FETAL DEVELOPMENT
 PTHrP IN PREGNANCIES COMPLICATED...
 PTHrP INVOLVEMENT IN THE...
 PTHrP AND THE CYTOKINE...
 CONCLUSION
 REFERENCES
 

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F. Meziani, A. Tesse, S. Welsch, H. Kremer, M. Barthelmebs, R. Andriantsitohaina, F. Schneider, and A. Gairard
Expression and Biological Activity of Parathyroid Hormone-Related Peptide in Pregnant Rat Uterine Artery: Any Role for 8-Iso-Prostaglandin F2{alpha}?
Endocrinology, February 1, 2008; 149(2): 626 - 633.
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