Extracellular Matrix in Preterm Premature Rupture of Fetal Membranes

Spontaneous preterm birth (sPTB) is a complex health problem that is at the center of intense international collaboration. Detailed understanding of this syndrome is critical to improve related maternal, fetal, newborn health outcomes worldwide. Clinically, the antecedents of sPTB include spontaneous preterm labor (sPTL) or preterm premature rupture of membranes (pPROM), which accounts for one-third of sPTB. The integrity of the amniochorionic membrane is dependent on the extracellular matrix (ECM), which plays a significant role in the function of amnion epithelial cells and the tissue as a whole. ECM proteins mainly include fibronectin, total fibrilar collagens, proteoglycans, hyaluronan, desmoplasia, biglycan and decorin. Abnormalities in the ECM have been related to pPROM, but this link deserves further investigation. In this review, we briefly summarize the components of the ECM, ECM proteins, the functional pathways involving ECM proteins, and their potential role in the pathophysiology of pPROM.


Introduction
Preterm birth (PTB) refers to live birth that occurs before 37 completed weeks of gestation. PTB is the principal cause of perinatal mortality and morbidity and the most common cause of death in children under 5 years old. PTB includes spontaneous preterm birth (sPTB) and indicated preterm birth (iPTB) in which birth is induced by medical reasons, such as intrauterine growth restriction, pre-eclampsia or fetal distress. sPTB may follow preterm labor (PTL) and subsequent membrane rupture and expulsion of the intrauterine contents. sPTB may also follow preterm premature rupture of fetal membranes (pPROM), which then leads in turn to labor and preterm birth. A portion of women with pPROM have labor induced for indication, including overt infection or fetal distress. Thus pPROM may lead to PTB along spontaneous and "indicated" pathways (e.g, GM-CSF, TNF-α, TGF-β, IL-1β, IL-6, IL-8, IL-10, etc.) [1].
The primary structure of the fetal membranes is the amnion composed of a monolayer epithelial cells, the basal (bottom, inner) border of which are in contact with amniotic fluid and at the apical (top, outer) border, a fundamentally collagen-rich layer of mesenchymal cells connected in turn to chorion [2]. The primary source of matrix and collagen support for the amnion is the mesenchymal cell layer. The elasticity, integrity and strength of fetal membranes is influenced by mesenchymal extracellular matrix (ECM) proteins and plays an essential role in preventing in pPROM. Dynamic changes of ECM can result in alterations in the components of the stroma, which sequentially affect cellular environments that lead to, for example, abnormal placentation or cervical insufficiency [4][5][6]. The catabolism and synthesis of ECM are strictly controlled by cytokines and growth factors, as well as via expression of chaperone proteins, and the function of proteolytic enzymes activators and inhibitors [7][8][9]. This review describes recent development in the study of ECM metabolism and structure that are relevant to the process of physiological and pathological parturitions.

ECM Composition and Structure
ECM proteins comprise the NC1 domains of basement membrane collagen IV and the C-terminal domains of fibril-forming collagens [10]. Collagen is a plentiful structural protein in humans.
It's the most abundant of the ECM, accounts for 3/4 dry weight of skin, comprises 1/3 the total protein. Many proteins include collagenous domains [11,12]. The fibrillin microfibril, along with elastin is present in the elastic fiber. The fibrillin microfibril is a key component of the tissue homeostasis sequestering and storing the potential forms of members of the BMP family and TGF-β [13][14][15].
Elastic fibers play key role in many tissues including lungs, skin, ligaments and arteries [16][17][18]. Tumor desmoplasia (fibrosis) is principally constituted of fibrillar collagens, secreted by both co-  Ⅶ represent a small fraction of the collagen in the fetal membrane ECM. However, in conjunction with types Ⅰand Ⅲ, they form a critical anchoring fibrillar structure. The different types of fibrillar collagens (types, Ⅱ, Ⅲ, XXIV and XXVⅡ) have different with their vulnerability to cleavage by matrix metalloproteinases (MMPs).

ECM Structural Components of the Fetal Membrane
MMPs participate in the action of physiological degradation and extracellular proteases [54]. Some MMPs family member have been found in the fetal membranes [55]. For example, type I collagen is less efficiently cleaved by MMP-1 than type Ⅲ collagen [56,57].
ECM proteins affect cell morphology behavior through signaling by cell surface receptors, mainly by MMPs [9]. The presence of specific memebrane ECM molecules is determined by the velocity of their synthesis and their degradation.

ECM and Associated Signaling and Cytokine Expression Pathways
Cells can sense ECM stiffening via integrins through cytoskeletal filaments that induce changes within the cell and manage cell migration. So, stiffer ECM can provoke manufacture of heparin sulfate proteoglycans, fibrin and from the other side to integrins, fibronectin as a glycoprotein of the ECM binding from one side to extracellular collagen [58]. ECM stiffening can also enhance cytoskeletal tension by Rho/ROCK signaling activation and increase cell-ECM adhesion connecting the ECM to the cytoskeleton by local adhesion proteins [59,60]. Fork head box O (FoxO) proteins regulate ECM remodeling, inflammation and apoptosis. FoxO1, FoxO3, and gene transcription and enzymatic activity [67,68]. In contrast, in vitro studies with amnion cells showed that either tumor necrosis factor-α(TNF-α)or interleukin-1β (IL-1β) can increase secretion of the MMP-9 proenzyme but not activation [69]. TNF-α binding to its receptor can activate caspases, degradation of ECM, and apoptosis in fetal membranes, which in turn promotes pPROM [70]. An increase expression of MMP-2 and MMP-9, and a decrease of expression of tissue inhibitors of TIMP-1 and TIMP2 can increase the risk of pPROM. This is likely important as some studies have shown that the overexpression of MMP-1 and MMP-9 can be mediated by IL-1β release from activated macrophages. An important cellular source of prostaglandins (PGs) in intrauterine tissues is the amnion [71]. PG, by upregulating MMP-9, also may participate in membrane rupture [72]. MMP-9 is likely a critical mediator in degradation of the ECM of fetal membranes in normal parturition [73]. MMP-9 preferentially targets basement membrane elastin, collagen (collagen Ⅳ), and fibronectin [74,75] and may also participate in fetal membrane rupture through degradation of type Ⅳ collagen. I L-1β is usually undetected in amniotic fluid during normal pregnancy, while IL-1β levels in amniotic fluid in preterm birth with and without infection is range from 100 to 2000 pg/ml [76,77]. IL-1β plays a key role in inducing expression of MMP-9 in amniochorion in response to lipopolysaccharide (LPS) stimulation [78]. Further, LPS provokes immune system cells via binding cellsurface Toll-like receptor 4 (TLR4) and activating protein kinase, such as p38 kinase and NF-κB, leading to an overexpression of proinflammatory cytokines, increased production of matrix-degrading enzymes and adhesion molecules [79]. TLR4 is generally expressed via the fetal membranes, placental trophoblasts and the female

American Journal of Biomedical Science & Research
Copy@ Nanbert Zhong reproductive tract [80][81][82]. In some cases, elevated levels of MMP-8 are thought to be the result of increased proinflammatory cytokine IL-6 in the context of infection-induced inflammation [83,84]. In other cases of such inflammation, the observed increase in intraamniotic lactic acid in the amniotic membrane suggests that an increase in anaerobic glycolysis may raise the production of MMP-8 thus weakening the maternal membrane [85]. However, the association between MMP-8 and IL-6 levels was unclear [85].

Pathophysiological Role of ECM in pPROM
Degradation of amniotic membrane ECM components, structural alterations in ECM and resulting biomechanical changes in the membranes [6] are hypothesized to participate in the pathway leading to membrane rupture at term and in pPROM.

Epigenetic Regulation of Long non-coding RNAs on the ECM in pPROM
Long non-coding RNAs (lncRNAs) are long single-stranded RNAs with no translational potential. LncRNAs function in regulating epigenetic and cellular processes through various mechanisms. By analyzing the present available studies of lncRNA transcripts within the reproductive system and the current understanding of the biology of lncRNAs, the important diagnostic and therapeutic roles of lncRNAs in the etiology of reproductive disorders have been illustrated [100]. LncRNA is a mediator of the outcomes of interaction at the maternal-fetal interface and in the biological mechanisms underlying trophoblast differentiation [101,102].
In addition to miscarriage, intrauterine grown retardation, preeclampsia, and gestational diabetes mellitus [103,104], a pathogenic role for lncRNA has been observed in human sPTB, wherein the epigenetic regulatory function of lncRNA was found to link social and environmental exposures and the outcome of pregnancy [105,106]. Down-regulation of lncRNAs on laminin, collagens, VLAα10, OPN, α6β1, and α/βDG, which also implied that these lncRNAs may be significant for the decreased synthesis of mRNA and leaded to weakening of the ECM. Several co-differentially expressed pairs of lncRNA-mRNA sharing the same genomic loci in sPTB were recognized as being associated with the infectioninflammation pathway and ubiquitine-proteasome system [107].

Conflict of Interest
No conflict of interest declared.