Next Article in Journal
Double Heterozygosity for BRCA1 Pathogenic Variant and BRCA2 Polymorphic Stop Codon K3326X: A Case Report in a Southern Italian Family
Next Article in Special Issue
Beyond the Matrix: The Many Non-ECM Ligands for Integrins
Previous Article in Journal
Halfway between 2D and Animal Models: Are 3D Cultures the Ideal Tool to Study Cancer-Microenvironment Interactions?
Previous Article in Special Issue
Mast Cells: Key Contributors to Cardiac Fibrosis
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Biological Role of Hyaluronan-Rich Oocyte-Cumulus Extracellular Matrix in Female Reproduction

Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, 27721 Libechov, Czech Republic
Int. J. Mol. Sci. 2018, 19(1), 283; https://doi.org/10.3390/ijms19010283
Submission received: 8 December 2017 / Revised: 16 January 2018 / Accepted: 16 January 2018 / Published: 18 January 2018
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

Abstract

:
Fertilization of the mammalian oocyte requires interactions between spermatozoa and expanded cumulus extracellular matrix (ECM) that surrounds the oocyte. This review focuses on key molecules that play an important role in the formation of the cumulus ECM, generated by the oocyte-cumulus complex. In particular, the specific inhibitors (AG1478, lapatinib, indomethacin and MG132) and progesterone receptor antagonist (RU486) exerting their effects through the remodeling of the ECM of the cumulus cells surrounding the oocyte have been described. After gonadotropin stimulus, cumulus cells expand and form hyaluronan (HA)-rich cumulus ECM. In pigs, the proper structure of the cumulus ECM depends on the interaction between HA and serum-derived proteins of the inter-alpha-trypsin inhibitor (IαI) protein family. We have demonstrated the synthesis of HA by cumulus cells, and the presence of the IαI, tumor necrosis factor-alpha-induced protein 6 and pentraxin 3 in expanding oocyte-cumulus complexes (OCC). We have evaluated the covalent linkage of heavy chains of IαI proteins to HA, as the principal component of the expanded HA-rich cumulus ECM, in porcine OCC cultured in medium with specific inhibitors: AG1478 and lapatinib (both inhibitors of epidermal growth factor receptor tyrosine kinase activity); MG132 (a specific proteasomal inhibitor), indomethacin (cyclooxygenase inhibitor); and progesterone receptor antagonist (RU486). We have found that both RU486 and indomethacin does not disrupt the formation of the covalent linkage between the heavy chains of IαI to HA in the expanded OCC. In contrast, the inhibitors AG1478 and lapatinib prevent gonadotropin-induced cumulus expansion. Finally, the formation of oocyte-cumulus ECM relying on the covalent transfer of heavy chains of IαI molecules to HA has been inhibited in the presence of MG132.

1. Extracellular Matrix in General

The extracellular matrix (ECM) is an important structure that is present in all tissues. The ECM interacts with cells to regulate a wide range of functions, including adhesion, proliferation, apoptosis and differentiation. The ECM can also locally release growth factors, such as epidermal growth factor (EGF), fibroblast growth factor and other signaling molecules such as transforming growth factor (TGFβ) and amphiregulin [1]. Naba et al. [2] defined ECM proteins of the mammalian matrisome by analysis of the human and mouse genome. It comprises 1–1.5% of the mammalian proteome. There are almost 300 proteins, including 43 collagen subunits, 36 proteoglycans (e.g., aggrecan, versican, perlecan and decorin) and ~200 complex glycoproteins (e.g., laminins, elastin, fibronectins, thrombospondins, tenascins or nidogen). Moreover, there are large numbers of ECM-modifying enzymes, ECM-binding growth factors, and other ECM-associated proteins [3]. Proteoglycans are important structural macromolecules in tissues. They consist of a core protein with attached glycosaminoglycan side chains. There are six types of glycosaminoglycans: chondroitin sulfate, dermatan sulfate, heparin sulfate, heparin, keratin sulfate and hyaluronan (HA). Hyaluronan is the only glycosaminoglycan synthesized at the cell membrane and it is present in a protein-free form [4]. The size of HA depends on the relative activity of HA-synthesizing and degrading enzymes. There are three hyaluronan synthase isoforms (HAS1, 2 and 3) [5]. The expression of the three HAS isoforms is regulated by various stimuli, suggesting different functions of the three proteins [6]. In contrast, hyaluronidases 1–4 degrade HA into several fragments with size-dependent functions [7]. Dysregulation of ECM structure causes tissue malfunction such as inflammation, infertility and cancer. The importance of the function of the ECM is demonstrated by the embryonic lethality caused by mutations in genes that encode components of the ECM [8,9].

2. Cumulus–Oophorus Extracellular Matrix in Ovarian Follicles: Characterization of Essential Components

It has been shown that the complex of heavy chains of inter-alpha-trypsin-inhibitor (IαI) to HA is the principal structural component of the cumulus ECM in ovarian follicles in mice [10,11] and pigs [12]. Genetic deletion of specific ECM proteins such as bikunin (light chain of IαI) and tumor necrosis factor alpha-induced protein 6 (Tnfaip6-null mice were unable to transfer heavy chains from IαI to HA) exhibit infertility in female mice [11,13]; see Table 1. Suzuki et al. [14] identified the full repertoire of the IαI deficiency-related genes from bikunin-knockout female mice. They suggested that proteins of the IαI family have additional effects on reproductive biology by modulating the expression of a large number of cellular genes.

2.1. IαI Family Proteins

It has been demonstrated that mice lacking intact IαI family proteins fail to form a stable cumulus ECM, and the naked ovulated oocytes are not fertilized in vivo [11]. Importantly, HA-rich oocyte-cumulus ECM does not form in IαI immune-depleted serum, while it does in the presence of purified IαI molecules [20]. The proper structure of the cumulus ECM depends on the interaction between HA and serum-derived proteins of the IαI family [11,12,21]. The IαI family proteins are synthesized and assembled in the liver and secreted into the blood at high concentrations (0.15–0.5 mg/mL of plasma) [35]. These IαI molecules consist of a small protein, named bikunin or light chain, with a chondroitin sulfate moiety that contains one or two evolutionarily related proteins, named heavy chains (HC1, HC2, and HC3). The first member, IαI, carries two heavy chains, HC1 and HC2, while the next two members, pre-α-inhibitor (PαI) and inter-α-like inhibitor (IαLI) have one heavy chain, i.e., HC, HC3 and HC2, respectively [36]. Positive bands of about 220, 130, and 120 kDa were detected in porcine serum [12] that likely correspond to IαI (bikunin plus HC1 and HC2), PαI (bikunin plus HC3), and IαLI (bikunin plus HC2), respectively [37,38]. In addition, porcine follicular fluids, collected at different stages of folliculogenesis were analyzed for the presence of IαI proteins [12]. Importantly, the levels of IαI molecules in porcine follicular fluid did not change in PMSG-primed follicles or in 8 h hCG-stimulated follicles, while a detectable increase in concentration was observed at 24 h post-hCG injection. In pigs, there is no apparent barrier to the transfer of IαI family molecules from the blood to the follicles, and the LH/hCG stimulation only facilitates their diffusion. Inside the follicle, the heavy chains are transferred from the glycosaminoglycan of IαI-related molecules to HA through a transesterification process [21]. To determine, whether HCs of serum-derived IαI-related molecules are covalently linked to HA in porcine expanded OCC in vivo, the experiments with OCC isolated from the antral follicles of pigs treated with PMSG (unexpanded OCC) or PMSG followed by hCG for 24 h (expanded OCC) were performed [12]. The authors found that expanded OCC contained positive bands of about 220, 130, and 120 kDa that likely correspond to IαI, PαI and IαLI, respectively [12,37,38]. After digestion of the expanded complexes with hyaluronidase, two additional immunopositive bands of about 85 kDa and 95 kDa were detected in the matrix extracts, the former likely corresponding to the relative molecular mass of single HC1 and HC2, and the latter to that of a single HC3 [36,39]. In addition, IαI proteins were detected in porcine OCC expanded in vitro after their culture in FSH- and serum-supplemented medium [12]. Interestingly, it has been shown that HCs from each IαI-related molecule identified in the serum are transferred and covalently linked to HA during the cumulus expansion of OCC. Analysis of the cumulus matrix and cell extracts clearly confirmed that the immunoreactivity was associated with the HA-rich cumulus ECM [12]. In mice and pigs [12,15,21], it has been confirmed that the covalent linkage of the heavy chains of IαI to HA is critical for cross-linking HA strands and stabilizing expanded HA-rich cumulus ECM.

2.2. TNFAIP6

It has been shown that the covalent transfer of heavy chains (HCs) of IαI proteins to HA does not occur in the OCC of Tnfaip6-null mice, indicating that TNFAIP6 is actively involved in this process [13]. TNFAIP6 is an inflammation-associated protein with the ability to bind HA, IαI, and other ligands and participate in the cumulus ECM formation and remodeling [40,41,42]. TNFAIP6 is produced by cumulus and granulosa cells after an ovulatory stimulus in mice, rats and pigs [13,18,24,25,26,27,28]. Previously, in pigs, four bands were detected with the antibody specific for TNFAIP6 in total and matrix protein extracts from OCC expanded in vivo. The major positive band had an apparent molecular weight of 35 kDa that also correlated well with the size of the free TNFAIP6 protein in mouse OCC. A doublet at ~120 kDa (HC-TNFAIP6 complex in mouse and pig) was also immunoreactive with the anti-TNFAIP6 antibody. In addition, the TNFAIP6 protein was detected in porcine OCC expanded in vitro after their culture in FSH- and serum-supplemented medium for 24 and 42 h [26]. It has been demonstrated that TNFAIP6, which binds to HA and interacts with heavy chains of IαI proteins, is another protein essential for the formation and stability of expanded HA-rich oocyte- cumulus ECM in mice and pigs [18,23,26]. Together with the high sequence similarity found among human, murine, rat, equine and porcine TNFAIP6 [23,25,27,28] and the expression of this protein and/or the respective gene in ovarian follicles of all of the examined species [18,23,25,26,27,28,43], it strongly supports the concept that TNFAIP6-mediated covalent binding of HCs (of IαI proteins) onto HA is a mechanism that mammalian OCC have in common [22].

2.3. PTX3

Experiments performed with Ptx3 knockout mice [29] have shown that complexes from Ptx3−/−mice have defective cumulus matrix organization. Interestingly, hormone stimulation of Ptx3−/−OCC in vitro showed that while cumulus cells synthesized HA at a normal rate they were unable to organize this polymer in the cumulus ECM [30]. PTX3 is essential protein for organizing the HA polymer in the cumulus ECM in mice [30,31,32]. PTX3 protein plays role in cumulus ECM assembly, where HCs transferred from IαI to HA by the catalytic activity of TNFAIP6 bind distinct protomers of multimeric PTX3 [33]. In pigs, PTX3 transcripts were significantly increased in OCC 24 h after in vivo hCG or in vitro FSH/LH stimulation [34]. Western blot analysis with PTX3 antibody revealed that cumulus ECM extracts from both in vivo hCG-stimulated pigs and in vitro FSH/LH-stimulated OCC cultured in medium supplemented either with follicular fluid or porcine serum, contain high levels of PTX3 protein. The localization of PTX3 protein in the porcine OCC was confirmed by immunostaining [34]. The mouse data concerning the integrity of HA-rich oocyte-cumulus ECM [30,31] together with porcine data [34] demonstrated the importance of PTX3 protein in the ovarian follicles.

3. Effect of Specific Inhibitors (AG1478, Lapatinib, Indomethacin and MG132) and Progesterone Receptor Antagonist (RU486) on the Formation of HA-Rich Cumulus Extracellular Matrix

3.1. Inhibition of EGFR Signaling Pathway (with AG1478) Affects Meiotic Maturation, Cumulus Expansion and Hyaluronan and Progesterone Synthesis

Several observations support the finding that EGF-like growth factors, i.e., amphiregulin and epiregulin, produced by granulosa cells and cumulus cells play a major role in triggering oocyte maturation and the cumulus expansion of OCC in mice [44]. Epidermal growth factor (EGF) is a poor inducer of porcine cumulus expansion in vitro [45]. Nevertheless, FSH pre-treatment strongly enhances EGF response within 3 h, as evidenced by a high increase in HA production and cumulus expansion after sequential exposure to FSH and EGF [46]. FSH itself does not affect epidermal growth factor receptor (EGFR) concentration or the tyrosine phosphorylation of EGFR, but it enhances the EGF-induced tyrosine phosphorylation of EGFR, indicating that the FSH signaling pathways may stimulate or modulate specific EGFR–regulating proteins. FSH also rapidly induces porcine OCC to express EGF-like growth factors [47] and TACE/ADAM17, a protease that cleaves and activates the EGF transmembrane precursors [48]. It has been shown [45] that AG1478, the inhibitor of EGFR tyrosine kinase activity, reduces 50% of the synthesis and 90% of the HA retained in the cumulus ECM, and prevents the expansion of porcine OCC stimulated with FSH for 24 h in vitro culture. Furthermore, although EGF does not stimulate progesterone production by porcine OCC and granulosa cells, the pre-treatment of both cell types with inhibitor AG1478, significantly reduces the stimulatory effect of FSH on progesterone production. This result is in agreement with the previous finding showing that AG1478 reduced the FSH-induced expression of the steroidogenic enzyme P450 side chain cleavage, Cyp11a1, in rat granulosa cells [49]. Importantly, the addition of AG1478 to the culture medium, irrespective of the stimulation, inhibited nuclear maturation in pigs [45,47]. Similarly, Ashkenazi et al. [50] observed that after the local administration of AG1478 inhibitor into the rat ovary, the ratio of entrapped immature oocytes (in germinal vesicle stage) in the inhibitor-treated ovaries was 5-fold higher than in the contralateral untreated ovaries. Thus, results in pigs [45] showing that EGFR activation by EGF-like growth factors produced under the FSH stimulus is involved in initiating the ovulatory events in porcine OCC are consistent with the results obtained in mice and rats [44,50]. However, it is possible that FSH trans-activates EGFR via mechanisms independent of EGF shedding [48]. Finally, it is important to note that the FSH-induced synthesis of both HA and progesterone is reduced but not abolished by AG1478, indicating that other signaling pathways elicited by FSH are operating in parallel [45].

3.2. Inhibition of EGFR Tyrosine Kinase (with Lapatinib) Affects Meiotic Maturation, Cumulus Expansion, and Expression of Cumulus-Associated Transcripts

In the ovarian follicles, EGFR mediates the ovulatory response to LH and the sustained activity of EGFR is an absolute requirement for LH-induced oocyte maturation and cumulus expansion [51]. However, abnormally elevated EGFR kinase activity can lead to various pathological states, including cancer. The human epidermal growth factor receptor (HER) family consists of four closely related transmembrane receptors: HER1 (human epidermal growth factor receptor 1, EGFR), HER2/c-Erb-B2, HER3/Erb-B3 and HER4/Erb-B4. These members of the type I receptor tyrosine kinase family are frequently implicated in cancer [52,53]. HER family-related downstream signaling plays a crucial role in cell proliferation, survival, migration and differentiation [54,55]. Recently, it has been investigated the effect of lapatinib on processes essential for ovulation, such as oocyte meiotic maturation and cumulus expansion, since it has been demonstrated that using of biological agents for treating cancer in women increases the probability that some women will conceive while taking the inhibitor (lapatinib) of growth factor signaling [56]. Lapatinib (GW572016, Tykerb/Tyverb; GlaxoSmithKline) is an orally active small molecule that reversibly and selectively inhibits the tyrosine kinase domain of both EGFR and HER2 [57] by binding to the ATP-binding site of the kinase, and preventing autophosphorylation or the rapid development of resistance to monotherapies [58]. It has been found that lapatinib, through the EGFR signaling pathway, is able to inhibit oocyte maturation in pigs [59]. In addition, lapatinib is able to reduce the expression of cumulus expansion -related transcripts (TNFAIP6, PTGS2), HA synthesis, cumulus expansion and progesterone secretion by porcine OCC cultured in FSH/LH supplemented medium [59]. This is in good agreement with the previous study showing the reduction of FSH-induced synthesis of both HA and progesterone by AG1478, another inhibitor of EGFR tyrosine kinase activity [45].

3.3. Addition of Progesterone Receptor Antagonist (RU486) to Culture Medium Affects Meiotic Maturation; It Does Not Affect Formation of Cumulus Extracellular Matrix Relying on the Covalent Transfer of Heavy Chains of IαI Molecules to Hyaluronan

Progesterone is an ovarian steroid hormone that regulates key aspects of female reproduction and acts through the progesterone receptor (PR). The progesterone receptor is a member of the nuclear receptor superfamily and functions as a ligand-activated transcription factor. The functional roles of PR in the ovary have been investigated with genetically modified mouse models and PR antagonist (RU486). It has been demonstrated that PR-knockout mice do not ovulate and are infertile [60,61]. Interestingly, despite the failure of ovulation in PR-null mice, cumulus expansion proceeds normally. However, the addition of RU486 to the culture medium with porcine OCC significantly decreases FSH/LH-induced resumption of oocyte meiosis (~74%; p < 0.05) and progression of oocyte maturation to the MII stage (~44%; p < 0.05) [62]. Gonadotropins stimulate cumulus expansion as well as HA synthesis by porcine OCC during in vitro maturation [19]. The addition of RU486 did not change FSH/LH-stimulated total HA synthesis; however, the retained amount of HA within the complexes was significantly reduced (p < 0.05). The amount of HA retained in cumulus ECM was approximately 60% of the amount retained within the cumulus ECM of the OCC cultured with FSH/LH alone [62]. However, the immunodetection of HABP, TNFAIP6, and PTX3 proteins in FSH/LH-stimulated OCC treated with RU486 confirmed the spatial localization of cumulus-associated components [62]. Furthermore, western blot analysis detected the heavy chains of IαI proteins in the matrix extracts of FSH/LH stimulated-OCC, treated with RU486 [62]. Shimada et al. found [63] that porcine OCC cultured in vitro in the presence of FSH/LH and RU486 had little developmental competence to proceed to the blastocyst stage. Moreover, RU486 significantly impaired blastocyst development in mice [64] and in cows [65]. Also, the administration of RU486 by intraperitoneal injection to gonadotropin-primed mice reduced the number of ovulated oocytes [66] and in mouse follicles cultured with hCG/EGF, in the presence of RU486, the MII rate was significantly lower (62%) [67]. Surprisingly the addition of RU486 to the culture medium significantly increased progesterone production by porcine OCC compared to FSH/LH alone [62]. To summarize, in pigs, the inhibition of PR with RU486 does not affect HA synthesis, the formation of cumulus ECM and covalent linkage between HA and heavy chains of IαI, but it appears that progesterone may be critical for maintaining an optimal microenvironment for oocyte maturation and fertilization [62].

3.4. Addition of General COX Inhibitor (Indomethacin) to Culture Medium does not Affect Meiotic Maturation, nor Formation of Cumulus Extracellular Matrix

In mammalian species, the preovulatory surge in gonadotropins upregulates the follicular expression of cyclooxygenase-2 (COX-2), which elevates the levels of prostaglandins [68,69]. Mice genetically deficient in Cox-2 exhibited ovulatory failure [70,71]. In addition, Cox-2 and prostaglandin E2 receptor subtype Ep2 null mice were infertile [72]. The administration of either general COX inhibitors (indomethacin) or inhibitors selective for COX-2 (NS-398, celecoxib) reduced ovulation rates in rodents, domestic animals, and monkeys [73,74,75]. In porcine OCC cultured in FSH/LH supplemented medium for 44 h, neither the resumption of meiosis (~87%) nor progression of oocyte maturation to MII (~72%) was affected by indomethacin [62]. Concomitantly, the total HA synthesis and retained amount of HA within the complexes was similar to those of OCC stimulated with FH/LH alone. In addition, the covalent binding between heavy chains of IαI molecules to HA in the cumulus ECM extracts, as well as cumulus ECM-related proteins (HABP, TNFAIP6, and PTX3) were detected in FSH/LH-stimulated OCC treated with indomethacin [62]. In agreement, indomethacin did not block HA synthesis induced by FSH in Graafian follicles in mice [76]. Moreover, Western blot analysis confirmed that in cumulus cells of Cox-2 and Ep2 null mice, the TNFAIP6 protein remained covalently associated with the heavy chains of IαI molecules. This is clear evidence that the ovaries of Cox-2 null mice maintain the capacity to produce Has2 mRNA in response to an ovulatory dose of hCG as well as the ability to form expanded cumulus ECM [72]. Matsumoto et al. [77] showed that the ovulatory process, but not follicular growth, oocyte maturation or fertilization, was primarily affected in adult Cox-2 or Ep2-deficient mice. Eppig [76] suggested that PGE2 might play a role in the indirect stimulation of cumulus expansion by LH. Interestingly, Ben-Ami et al. [78] have shown that LH may mediate its effects on COX-2 expression in cumulus cells via the induction of the EGF-related factors amphiregulin, epiregulin, and betacelulin produced in human granulosa cells. Similarly, in mice, these factors bind EGF receptor in cumulus cells and induce the Cox-2 message [79]. Also Hsieh et al. [80] have demonstrated that in mice, the LH-induction of Cox-2/Ptgs2 expression is dependent on the activation of EGF receptor signaling in cumulus and mural granulosa cells. Moreover, it has been shown that lapatinib, the inhibitor of EGFR tyrosine kinase activity, reduces the expression of COX-2 mRNA in porcine OCC cultured in vitro [59]. To summarize, in pigs, the inhibition of COX-2 by indomethacin does not affect FSH/LH-stimulated HA synthesis and the formation of the covalent linkage between heavy chains of IαI to HA nor progesterone production by cultured OCC [62].

3.5. Inhibition of Proteasomal Proteolysis (with MG132) Strongly Affects Meiotic Maturation and Formation of Cumulus Extracellular Matrix

Protein turnover mediated by the ubiquitin-proteasome pathway plays an essential role in cell physiology and pathology. Ubiquitin is a small chaperone protein that forms covalently linked isopeptide chains on protein substrates to mark them for degradation by the 26S proteasome. The 26S proteasome is a multicatalytic protease complex that specifically recognizes and hydrolyzes proteins tagged with multiubiquitin chains. The subunits of the 26S proteasome comprise approximately 1% of the total proteome in mammalian cells; the ubiquitin-proteasome pathway serves as the main substrate-specific cellular protein degradation pathway [81,82,83]. MG132 is a cell-permeable peptide aldehyde that inhibits the chymotrypsin-like activity of the 20S proteasomal core [84,85]. The ubiquitin–proteasome pathway modulates mouse oocyte meiotic maturation and fertilization via regulation of the MAPK-cascade and cyclin B1 degradation [86,87]. In addition, the role of the 26S proteasome in the regulation of oocyte meiosis has been described in mammals, specifically rats, mice and pigs [83,88,89,90]. In pigs, the addition of MG132 to the gonadotropin-supplemented medium prevented cumulus expansion and significantly reduced HA synthesis by the cumulus cells. Moreover, the covalent binding between HA and heavy chains of IαI was not detected in the MG132-treated porcine OCC [89]. The formation of expanded HA-rich cumulus ECM depends on HA association with specific hyaluronan-binding proteins [41], such as IαI [12,20], TNFAIP6 [23,24,25,26,27] and PTX3 [30,34], which all have been detected in mice and pigs. The TNFAIP6-HC complex is likely a catalyst in the transfer of heavy chains (of IαI) onto HA [91]. This mediator reacts rapidly with any HA, leading to the formation of heavy chain-HA and release of the TNFAIP6 catalyst. While the mRNA expression of HAS2 and TNFAIP6 in the gonadotropin-stimulated OCC was increased in pigs [27], mice [17,23], and rats [25], in the presence of MG132, the expression of HAS2 and TNFAIP6 was markedly suppressed in porcine OCC. In addition no signal of HA was observed by immunostaining in porcine OCC [92]. Tsafriri et al. [93] used a broad-spectrum metalloprotease inhibitor, GM6001, to find whether proteolytic activity was involved in the action of LH on the resumption of meiosis in rats. His conclusion was that this inhibitor prevented the LH-induced resumption of meiosis. In agreement, the inhibition of proteasomal proteolysis with MG132 arrested 90% of porcine oocytes in the germinal vesicle stage. Moreover, MG132 blocked the degradation of F-actin-rich transzonal projections (TZPs) interconnecting cumulus cells with the oocyte and cumulus expansion in pigs [89]. The resumption of oocyte meiosis was accompanied by the disappearance of the zona pellucida-spanning and actin microfilament-rich TZPs, and an alteration of gap junction communication [16,89,94]. Since the maintenance of TZPs supports an oocyte meiotic block and porcine OCC treated with MG132 remain unexpanded, it has been suggested that proteasomal proteolysis participates in the process of the resumption of meiosis. The terminal differentiation of cumulus oophorus within the ovarian follicle plays a crucial role in the ability of the oocyte to resume meiosis and reach full developmental competence [95,96,97]. Progesterone has been shown to enhance the activity of proteolytic enzymes important for the rupture of the follicular wall at ovulation [98]. Gonadotropins induce PR expression in cumulus cells concomitantly with an increase in progesterone secretion by porcine OCC [99,100]. The involvement of the proteasome in the turnover of StAR has been described [101,102,103] with subsequent influence on progesterone synthesis [102]. The transfer of cholesterol across the mitochondrial membranes is promoted by StAR [104]. In MG132-treated porcine OCC the progesterone levels were reduced [92]. In contrast, Tajima et al. [102] found a significant elevation in progesterone synthesis in MG132-treated rat granulosa cells. This discrepancy can be explained by the differences in the cell culture regimen. The relation between progesterone and proteolytic enzyme activity during ovulation in the gonadotropin-treated immature rat ovary was studied by Iwamasa et al. [98]. Their results suggested that progesterone played an indispensable role during the first 4 h of the ovulatory process by regulating proteolytic enzyme activities. Our results showed that the ability of gonadotropin-stimulated porcine cumulus cells to produce progesterone to a level comparable with control OCC was not restored when MG132 was present for 20 h of the culture, but it was restored (50%) when MG132 was only present for 3 h. In summary, the specific proteasomal inhibitor MG132 prevents the gonadotropin-induced resumption of meiosis and subsequent cumulus expansion. In addition, it protects TZPs against breakdown, affects the terminal differentiation of cumulus cells, markedly reduces the expression of HAS2 and TNFAIP6 and prevents the formation of a covalent linkage between HA and the heavy chains of IαI [89,92].

4. Conclusions

Ovulation is controlled through multiple inputs including endocrine hormones, immune and metabolic signals, as well as intra-follicular paracrine factors from the theca, mural and cumulus granulosa cells and the oocyte itself. The ovulatory mediators exert their effects through remodeling of the cumulus ECM that surrounds the oocyte. The proper structure of the cumulus ECM, which is essential for ovulation, transport of the OCC to the oviduct and fertilization depends on the interaction between HA and HA-associated ECM proteins. HA cross-linking within the cumulus ECM represents an important new mechanism in the regulation of the ovulatory process in mammalian follicles. We suggest that the structural changes in cumulus ECM affect signaling pathways and consequently the resumption of meiosis. In addition, it is interesting to note that the synthesis of ECM molecules is controlled by specific growth factors and the life of ECM molecules is determined by proteases. Thus, growth factors signaling pathways and the control of ECM turnover by proteases become possible targets for new therapies.

Acknowledgments

This work was supported by EXCELENCE CZ.02.1.01/0.0/0.0/15_003/0000460 OP RDE; Institutional Research Concept RV067985904. I did not receive any funds for covering the costs to publish the manuscript in open access.

Author Contributions

I appreciate help of all people who have been involved in this research.

Conflicts of Interest

The author declares no conflict of interest.

Abbreviations

ECMExtracellular matrix
HAHyaluronan
IαIInter-alpha-trypsin inhibitor
TNFAIP6Tumor necrosis factor alpha-induced protein 6
PTX3Pentraxin 3
OCCOocyte-cumulus complexes
COX2/PTGS2Cyclooxygenase/prostaglandin endoperoxide synthase
EGFEpidermal growth factor
EGFREpidermal growth factor receptor
GVBDGerminal vesicle breakdown
M IMetaphase I
M IIMetaphase II
hCGHuman chorion gonadotropin
PMSGPregnant mare gonadotropin
TFGβTransforming growth factor beta

References

  1. Theocharis, A.D.; Skandalis, S.S.; Gialeli, C.; Karamanos, N.K. Extracellular matrix structure. Adv. Drug Deliv. Rev. 2016, 97, 4–27. [Google Scholar] [CrossRef] [PubMed]
  2. Naba, A.; Clauser, K.R.; Hoersch, S.; Liu, H.; Carr, S.A.; Hynes, R.O. The matrisome: In silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices. Mol. Cell. Proteomics 2012, 11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Hynes, R.O.; Naba, A. Overview of the matrisome—An inventory of extracellular matrix constituents and functions. Cold Spring Harb. Perspect. Biol. 2012, 4. [Google Scholar] [CrossRef] [PubMed]
  4. Theocharis, A.D.; Skandalis, S.S.; Tzanakakis, G.N.; Karamanos, N.K. Proteoglycans in health and disease: Novel roles for proteoglycans in malignancy and their pharmacological targeting. FEBS J. 2010, 277, 3904–3923. [Google Scholar] [CrossRef] [PubMed]
  5. Itano, N.; Sawai, T.; Yoshida, M.; Lenas, P.; Yamada, Y.; Imagawa, M.; Shinomura, T.; Hamaguchi, M.; Yoshida, Y.; Ohnuki, Y.; et al. Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties. J. Biol. Chem. 1999, 274, 25085–25092. [Google Scholar] [CrossRef] [PubMed]
  6. Jacobson, A.; Brinck, J.; Briskin, M.J.; Spicer, A.P.; Heldin, P. Expression of human hyaluronan synthases in response to external stimuli. Biochem. J. 2000, 348 Pt 1, 29–35. [Google Scholar] [CrossRef] [PubMed]
  7. Stern, R.; Jedrzejas, M.J. Hyaluronidases: Their genomics, structures, and mechanisms of action. Chem. Rev. 2006, 106, 818–839. [Google Scholar] [CrossRef] [PubMed]
  8. Jarvelainen, H.; Sainio, A.; Koulu, M.; Wight, T.N.; Pentinen, R. Extracellular matrix molecules: Potential targets in pharmacotherapy. Pharmacol. Rev. 2009, 61, 198–223. [Google Scholar] [CrossRef] [PubMed]
  9. Bateman, J.F.; Boot-Handford, R.P.; Lamande, S.R. Genetic diseases of connective tissues: Cellular and extracellular effects of ECM mutations. Nat. Rev. Gen. 2009, 10, 173–183. [Google Scholar] [CrossRef] [PubMed]
  10. Chen, L.; Mao, S.J.; McLean, L.R.; Powers, R.W.; Larsen, W.J. Proteins of the inter-alpha-trypsin inhibitor family stabilize the cumulus extracellular matrix through their direct binding with hyaluronic acid. J. Biol. Chem. 1994, 269, 28282–28287. [Google Scholar] [PubMed]
  11. Zhuo, L.; Yoneda, M.; Zhao, M.; Yingsung, W.; Yoshida, N.; Kitagawa, Y.; Kawamura, K.; Suzuki, T.; Kimata, K. Defect in SHAP-hyaluronan complex causes severe female infertility. A study by inactivation of the bikunin gene in mice. J. Biol. Chem. 2001, 276, 7693–7696. [Google Scholar] [CrossRef] [PubMed]
  12. Nagyova, E.; Camaioni, A.; Prochazka, R.; Salustri, A. Covalent transfer of heavy chains of inter-alpha-trypsin inhibitor family proteins to hyaluronan in in vivo and in vitro expanded porcine oocyte-cumulus complexes. Biol. Reprod. 2004, 71, 1838–1843. [Google Scholar] [CrossRef] [PubMed]
  13. Fulop, C.; Szanto, S.; Mukhopadhyay, D.; Bardos, T.; Kamath, R.V.; Rugg, M.S.; Day, A.J.; Salustri, A.; Hascall, V.C.; Glant, T.T.; et al. Impaired cumulus mucification and female sterility in tumor necrosis factor-induced protein 6 deficient mice. Development 2003, 130, 2253–2261. [Google Scholar] [CrossRef] [PubMed]
  14. Suzuki, M.; Kobayashi, H.; Tanaka, Y.; Kanayama, N.; Terao, T. Reproductive failure in mice lacking inter-alpha-trypsin inhibitor (ITI)-ITI target genes in mouse ovary identified by microarray analysis. J. Endocrinol. 2004, 183, 29–38. [Google Scholar] [CrossRef] [PubMed]
  15. Salustri, A.; Yanagishita, M.; Hascall, V.C. Synthesis and accumulation of hyaluronic acid and proteoglycans in the mouse cell-oocyte complex during follicle-stimulating hormone-induced mucification. J. Biol. Chem. 1989, 264, 13840–13847. [Google Scholar] [PubMed]
  16. Chen, L.; Wert, S.E.; Hendrix, E.M.; Russell, P.T.; Cannon, M.; Larsen, W.J. Hyaluronic acid synthesis and gap junction endocytosis are necessary for normal expansion of the cumulus mass. Mol. Reprod. Dev. 1990, 26, 236–247. [Google Scholar] [CrossRef] [PubMed]
  17. Fulop, C.; Salustri, A.; Hascall, V.C. Coding sequence of a hyaluronan synthase homologue expressed during expansion of the mouse cumulus-oocyte complex. Arch. Biochem. Biophys. 1997, 337, 261–266. [Google Scholar] [CrossRef] [PubMed]
  18. Carrette, O.; Nemade, R.V.; Day, A.J.; Brickner, A.; Larsen, W.J. TSG-6 is concentrated in the extracellular matrix of mouse cumulus oocyte complexes through hyaluronan and inter-alpha-inhibitor binding. Biol. Reprod. 2001, 65, 301–308. [Google Scholar] [CrossRef] [PubMed]
  19. Nagyová, E.; Procházka, R.; Vanderhyden, B.C. Ooocytectomy does not influence synthesis of hyaluronic acid by pig cumulus cells: Retention of hyaluronic acid after insulin-like growth factor-I treatment in serum free-medium. Biol. Reprod. 1999, 61, 569–574. [Google Scholar] [CrossRef] [PubMed]
  20. Chen, L.; Mao, S.J.; Larsen, W.J. Identification of a factor in foetal bovine serum that stabilizes the cumulus extracellular matrix. A role for a member of the inter-alpha-trypsin inhibitor family. J. Biol. Chem. 1992, 267, 12380–12386. [Google Scholar] [PubMed]
  21. Chen, L.; Zhang, H.; Powers, R.W.; Russell, P.T.; Larsen, W.J. Covalent linkage between proteins of the inter-a-inhibitor family and hyaluronic acid is mediated by a factor produced by granulosa cells. J. Biol. Chem. 1996, 271, 19409–19414. [Google Scholar] [CrossRef] [PubMed]
  22. Nagyova, E. Organization of the expanded cumulus-extracellular matrix in preovulatory follicles: A role for inter-alpha-trypsin inhibitor. Endocr. Regul. 2015, 49, 37–45. [Google Scholar] [CrossRef] [PubMed]
  23. Fulop, C.; Kamath, R.V.; Li, Y.; Otto, J.M.; Salustri, A.; Olsen, B.R.; Glant, T.T.; Hascall, V.C. Coding sequence, exon-intron structure and chromosomal localization of murine TNF-stimulated gene 6 that is specifically expressed by expanding cumulus cell-oocyte complexes. Gene 1997, 202, 95–102. [Google Scholar] [CrossRef]
  24. Mukhopadhyay, D.; Hascall, V.C.; Day, A.J.; Salustri, A.; Fulop, C. Two distinct populations of tumor necrosis factor-stimulated gene-6 protein in the extracellular matrix of expanded mouse cumulus cell-oocyte complexes. Arch. Biochem. Biophys. 2001, 394, 173–181. [Google Scholar] [CrossRef] [PubMed]
  25. Yoshioka, S.; Ochsner, S.; Russell, D.L.; Ujioka, T.; Fujii, S.; Richards, J.S.; Espey, L.L. Expression of tumor necrosis factor -stimulated gene-6 in the rat ovary in response to an ovulatory dose of gonadotropin. Endocrinology 2000, 141, 4114–4119. [Google Scholar] [CrossRef] [PubMed]
  26. Nagyova, E.; Camaioni, A.; Prochazka, R.; Day, A.J.; Salustri, A. Synthesis of tumor necrosis factor alpha-induced protein 6 in porcine preovulatory follicles: A study with A38 antibody. Biol. Reprod. 2008, 78, 903–909. [Google Scholar] [CrossRef] [PubMed]
  27. Nagyova, E.; Nemcova, L.; Prochazka, R. Expression of tumor necrosis factor alpha-induced protein 6 messenger RNA in porcine preovulatory ovarian follicles. J. Reprod. Dev. 2009, 55, 231–235. [Google Scholar] [CrossRef] [PubMed]
  28. Sayasith, K.; Dore, M.; Sirois, J. Molecular characterization of tumor necrosis alpha-induced protein 6 and its human choret alionic gonadotropin-dependent induction in theca and mural granulosa cells of equine preovulatory follicles. Reproduction 2007, 133, 135–145. [Google Scholar] [CrossRef] [PubMed]
  29. Varani, S.; Elvin, J.A.; Yan, C.; De Mayo, J.; DeMayo, F.J.; Horton, H.F.; Byrne, M.C.; Matzuk, M.M. Knockout of pentraxin 3, a downstream target of growth differentiation factor-9, causes female subfertility. Mol. Endocrinol. 2002, 16, 1154–1167. [Google Scholar] [CrossRef] [PubMed]
  30. Salustri, A.; Garlanda, C.; Hirsch, E.; De Acetis, M.; Taccagno, A.; Bottazzi, B.; Doni, A.; Bastone, A.; Mantovani, G.; Beck Peccoz, P.; et al. PTX3 plays a key role in the organization of the cumulus oophorus extracellular matrix and in in vivo fertilization. Development 2004, 131, 1577–1586. [Google Scholar] [CrossRef] [PubMed]
  31. Scarchilli, L.; Camaioni, A.; Bottazzi, B.; Negri, V.; Doni, A.; Deban, L.; Bastone, A.; Salvatori, G.; Mantovani, A.; Siracusa, G.; et al. PTX3 interacts with inter-alpha-trypsin inhibitor: Implications for hyaluronan organization and cumulus oophorus expansion. J. Biol. Chem. 2007, 282, 30161–30170. [Google Scholar] [CrossRef] [PubMed]
  32. Ievoli, E.; Lindstedt, R.; Inforzato, A.; Camaioni, A.; Palone, F.; Day, A.J.; Mantovani, A.; Salvatori, G.; Salustri, A. Implications of the oligomeric state of the N-terminal PTX3 domain in cumulus matrix assembly. Matrix Biol. 2011, 30, 330–337. [Google Scholar] [CrossRef] [PubMed]
  33. Inforzato, A.; Rivieccio, V.; Morreale, A.P.; Bastone, A.; Salustri, A.; Scarchilli, L.; Verdoliva, A.; Vincenti, S.; Gallo, G.; Chiapparino, C.; et al. Structural characterization of PTX3 disulfide bond network and its multimeric status in cumulus matrix organization. J. Biol. Chem. 2008, 283, 10147–10161. [Google Scholar] [CrossRef] [PubMed]
  34. Nagyova, E.; Kalous, J.; Nemcova, L. Increased expression of pentraxin 3 after in vivo and in vitro stimulation with gonadotropins in porcine oocyte-cumulus complexes and mural granulosa cells. Domest. Anim. Endocrinol. 2016, 56, 29–35. [Google Scholar] [CrossRef] [PubMed]
  35. Mizon, C.; Balduyck, M.; Albani, D.; Michalski, C.; Burnouf, T.; Mizon, J. Development of an enzyme-linked immunosorbent assay for human plasma inter-alpha-trypsin inhibitor (ITI) using specific antibodies against each of the H1 and H2 heavy chains. Immunol. Methods 1996, 190, 61–70. [Google Scholar] [CrossRef]
  36. Salier, J.P.; Rouet, P.; Raguenez, G.; Daveau, M. The inter-a-inhibitor family: From structure to regulation. Biochem. J. 1996, 315, 1–9. [Google Scholar] [CrossRef] [PubMed]
  37. Rouet, P.; Daveau, M.; Salier, J.P. Electrophoretic pattern of the inter-alpha-inhibitor family proteins in human serum characterized by chain-specific antibodies. Biol. Chem. Hoppe-Seyler 1992, 373, 1019–1024. [Google Scholar] [CrossRef] [PubMed]
  38. Carrette, O.; Mizon, C.; Sautiere, P.; Sesboue, R.; Mizon, J. Purification and characterization of pig inter-a-inhibitor and its constitutive heavy chains. Biochem. Biophys. Acta 1997, 1338, 21–30. [Google Scholar] [CrossRef]
  39. Flahaut, C.; Capon, C.; Balduyck, M.; Ricart, G.; Sautiere, P.; Mizon, J. Glycosylation pattern of human inter-alpha-inhibitor heavy chains. Biochem. J. 1998, 333 Pt 3, 749–756. [Google Scholar] [CrossRef] [PubMed]
  40. Milner, C.M.; Day, A.J. TSG-6: A multifunctional protein associated with inflammation. J. Cell Sci. 2003, 116, 1863–1873. [Google Scholar] [CrossRef] [PubMed]
  41. Day, A.J.; de la Motte, C.A. Hyaluronan cross-linking: A protective mechanism in inflammation? Trends Immunol. 2005, 28, 637–643. [Google Scholar] [CrossRef] [PubMed]
  42. Milner, C.M.; Higman, V.A.; Day, A.J. TSG-6: A pluripotent inflammatory mediator? Biochem. Soc. Trans. 2006, 34, 446–450. [Google Scholar] [CrossRef] [PubMed]
  43. Jessen, T.E.; Odum, L. Role of tumour necrosis factor stimulated gene 6 (TSG-6) in the coupling of inter-alpha-trypsin inhibitor to hyaluronan in human follicular fluid. Reproduction 2003, 125, 27–31. [Google Scholar] [CrossRef] [PubMed]
  44. Conti, M.; Hsieh, M.; Park, J.Y.; Su, Y.Q. Role of the epidermal growth factor network in ovarian follicles. Mol. Endocrinol. 2006, 20, 715–723. [Google Scholar] [CrossRef] [PubMed]
  45. Nagyova, E.; Camaioni, A.; Scsukova, S.; Mlynarcikova, A.; Prochazka, R.; Nemcova, L.; Salustri, A. Activation of Cumulus Cell SMAD2/3 and Epidermal Growth Factor Receptor Pathways Are Involved in Porcine Oocyte-Cumulus Cell Expansion and Steroidogenesis. Mol. Reprod. Dev. 2011, 78, 391–402. [Google Scholar] [CrossRef] [PubMed]
  46. Prochazka, R.; Kalab, P.; Nagyova, E. Epidermal growth factor-receptor tyrosine kinase activity regulates expansion of porcine oocyte-cumulus cell complexes in vitro. Biol. Reprod. 2003, 68, 797–803. [Google Scholar] [CrossRef] [PubMed]
  47. Procházka, R.; Petlach, M.; Nagyová, E.; Nemcová, L. Effect of epidermal growth factor-like peptides on pig cumulus cell expansion, oocyte maturation, and acquisition of developmental competence in vitro: Comparison with gonadotropins. Reproduction 2011, 141, 425–435. [Google Scholar] [CrossRef] [PubMed]
  48. Yamashita, Y.; Kawashima, I.; Yanai, Y.; Nishibori, M.; Richards, J.S.; Shimada, M. Hormone-induced expression of tumor necrosis factor alpha converting enzyme/A disintegrin and metaloprotease-17 impacts porcine cumulus cell oocyte complex expansion and meiotic maturation via ligand activation of the epidermal growth factor receptor. Endocrinology 2007, 148, 6164–6175. [Google Scholar] [CrossRef] [PubMed]
  49. Wayne, C.M.; Fan, H.Y.; Cheng, X.; Richards, J.S. Follicle-stimulating hormone induces multiple signaling cascades: Evidence that activation of Rous sarcoma oncogene, RAS, and the epidermal growth factor receptor are critical for granulosa cell differentiation. Mol. Endocrinol. 2007, 21, 1940–1957. [Google Scholar] [CrossRef] [PubMed]
  50. Ashkenazi, H.; Cao, X.; Motola, S.; Popliker, M.; Conti, M.; Tsafriri, A. Epidermal growth factor family members: Endogenous mediators of the ovulatory response. Endocrinology 2005, 46, 77–84. [Google Scholar] [CrossRef] [PubMed]
  51. Reizel, Y.; Elbaz, Y.; Dekel, N. Sustained activity of the EGF receptor is an absolute requisite for LH-induced oocyte maturation and cumulus expansion. Mol. Endocrinol. 2010, 24, 402–411. [Google Scholar] [CrossRef] [PubMed]
  52. Srinivasan, R.; Benton, E.; McCormick, F.; Thomas, H.; Gullick, W.J. Expression of the c-erbB-3/HER-3 and c-erbB-4/HER-4 growth factor receptors and their ligands, neuregulin-1 alpha, neuregulin-1 beta, and betacellulin, in normal endometrium and endometrial cancer. Clin. Cancer Res. 1999, 5, 2877–2883. [Google Scholar] [PubMed]
  53. Santin, A.D.; Bellone, S.; Gokden, M.; Palmieri, M.; Dunn, D.; Agha, J. Overexpression of HER-2/neu in uterine serous papillary cancer. Clin. Cancer Res. 2002, 8, 1271–1279. [Google Scholar] [PubMed]
  54. Yarden, Y.; Sliwkowski, M.X. Untangling the ErbB signaling network. Nat. Rev. Mol. Cell Biol. 2001, 2, 127–137. [Google Scholar] [CrossRef] [PubMed]
  55. Baselga, J.; Arteaga, C.L. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J. Clin. Oncol. 2005, 23, 2445–2459. [Google Scholar] [CrossRef] [PubMed]
  56. Kelly, H.; Graham, M.; Humes, E. Delivery of a healthy baby after first-trimester maternal exposure to lapatinib. Clin. Breast Cancer 2006, 7, 339–341. [Google Scholar] [CrossRef] [PubMed]
  57. Rusnak, D.W.; Lackey, K.; Affleck, K.; Wood, E.R.; Alligood, K.J.; Rhodes, N. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol. Cancer Ther. 2001, 1, 85–94. [Google Scholar] [PubMed]
  58. Eccles, S. The epidermal growth factor receptor /Erb-B/HER family in normal and malignant breast biology. Int. J. Dev. Biol. 2011, 55, 685–696. [Google Scholar] [CrossRef] [PubMed]
  59. Nagyova, E.; Nemcova, L.; Mlynarcikova, A.; Scsukova, S.; Kalous, J. Lapatinib inhibits meiotic maturation of porcine oocyte-cumulus complexes cultured in vitro in gonadotropin -supplemented medium. Fertil. Steril. 2013, 99, 1739–1748. [Google Scholar] [CrossRef] [PubMed]
  60. Lydon, J.P.; DeMayo, F.J.; Funk, C.R.; Mani, S.K.; Hughes, A.R.; Montgomery, C.A., Jr.; Shyamala, G.; Conneely, O.M.; O’Malley, B.W. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 1995, 9, 2266–2278. [Google Scholar] [CrossRef] [PubMed]
  61. Faivre, E.J.; Daniel, A.R.; Hillard, C.H.J.; Lange, C.A. Progesterone receptor rapid signaling mediates serine 345 phosphorylation and tethering to specificity protein 1 transcription factors. Mol. Endocrinol. 2008, 22, 823–837. [Google Scholar] [CrossRef] [PubMed]
  62. Nagyova, E.; Scsukova, S.; Kalous, J.; Mlynarcikova, A. Effect of RU486 and indomethacin on meiotic maturation, formation of extracellular matrix, and progesterone production by porcine oocyte-cumulus complexes. Domest. Anim. Endocrinol. 2014, 48, 7–14. [Google Scholar] [CrossRef] [PubMed]
  63. Shimada, M.; Nishibori, M.; Yamashita, Y.; Ito, J.; Mori, T.; Richards, J.S. Down-regulated expression of A disintegrin and metalloproteinase with thrombospondin-like repeats-1 by progesterone receptor antagonist is associated with impaired expansion of porcine cumulus-oocyte complexes. Endocrinology 2004, 145, 4603–4614. [Google Scholar] [CrossRef] [PubMed]
  64. Roh, S.I.; Batten, B.E.; Friedman, C.I.; Kim, M.H. The effects of progesterone antagonist RU486 on mouse oocyte maturation, ovulation, fertilization, and cleavage. Am. J. Obstet. Gynecol. 1988, 159, 1584–1589. [Google Scholar] [CrossRef]
  65. Aparicio, I.M.; Garcia-Herreros, M.; O’Shea, L.C.; Hensey, C.; Lonergan, P.; Fair, T. Expression, regulation, and function of progesterone receptors in bovine cumulus oocyte complexes during in vitro maturation. Biol. Reprod. 2011, 84, 910–921. [Google Scholar] [CrossRef] [PubMed]
  66. Shao, R.; Markström, E.; Friberg, P.A.; Johansson, M.; Billig, H. Expression of progesterone receptor (PR) A and B isoforms in mouse granulosa cells: Stage-dependent PR-mediated regulation of apoptosis and cell proliferation. Biol. Reprod. 2003, 68, 914–921. [Google Scholar] [CrossRef] [PubMed]
  67. Romero, S.; Smitz, J. Epiregulin can effectively mature isolated cumulus-oocyte complexes, but fails as a substitute for the hCG/epidermal growth factor stimulus on cultured follicles. Reproduction 2009, 137, 997–1005. [Google Scholar] [CrossRef] [PubMed]
  68. Sirois, J. Induction of prostaglandin endoperoxide synthase-2 by human chorionic gonadotropin in bovine preovulatory follicles in vivo. Endocrinology 1994, 135, 841–848. [Google Scholar] [CrossRef] [PubMed]
  69. Nuttinck, F.; Reinaud, P.; Tricoire, H.; Vigneron, C.; Peynot, N.; Mialot, J.P.; Mermillod, P.; Charpigny, G. Cyclooxygenase-2 is expressed by cumulus cells during oocyte maturation in cattle. Mol. Reprod. Dev. 2002, 61, 93–101. [Google Scholar] [CrossRef] [PubMed]
  70. Davis, B.J.; Lennard, D.E.; Lee, C.A.; Tiano, H.F.; Morham, S.G.; Wetsel, W.C.; Langenbach, R. Anovulation in cyclooxygenase-2-deficient mice is restored by prostaglandin E(2) and interleukin-1 beta. Endocrinology 1999, 140, 2685–2695. [Google Scholar] [CrossRef] [PubMed]
  71. Lim, H.; Paria, B.C.; Das, S.K.; Dinchuc, J.E.; Langebach, R.; Trzaskos, J.M.; Dey, S.K. Multiple female reproductive failures in cyclooxygenase 2- deficient mice. Cell 1997, 91, 197–208. [Google Scholar] [CrossRef]
  72. Ochsner, S.A.; Russell, D.L.; Day, A.J.; Breyer, R.M.; Richards, J.S. Decreased expression of tumor necrosis factor-alpha-stimulated gene 6 in cumulus cells of the cyclooxygenase-2 and EP2 null mice. Endocrinology 2003, 144, 1008–1019. [Google Scholar] [CrossRef] [PubMed]
  73. Janson, P.O.; Brannstrom, M.; Holmes, P.V.; Sogn, J. Studies on the mechanism of ovulation using the model of the isolated ovary. Ann. N. Y. Acad. Sci. 1988, 541, 22–29. [Google Scholar] [CrossRef] [PubMed]
  74. Peters, M.W.; Pursley, J.R.; Smith, G.W. Inhibition of intrafollicular PGE2 synthesis and ovulation following ultrasound-mediated intrafollicular injection of the selective cyclooxygenase-2 inhibitor NS-398 in cattle. J. Anim. Sci. 2004, 82, 1656–1662. [Google Scholar] [CrossRef] [PubMed]
  75. Duffy, D.M.; VandeVoort, C.A. Maturation and fertilization of non-human primate oocytes are compromised by oral administration of a COX-2 inhibitor. Fertil. Steril. 2011, 95, 1256–1260. [Google Scholar] [CrossRef] [PubMed]
  76. Eppig, J.J. Prostaglandin E2 stimulates cumulus expansion and hyaluronic acid synthesis by cumuli oophori isolated from mice. Biol. Reprod. 1981, 25, 191–195. [Google Scholar] [CrossRef] [PubMed]
  77. Matsumoto, H.; Ma, W.G.; Smalley, W.; Trzaskos, J.; Breyer, R.M.; Dey, S.K. Diversification cyclooxygenase-2-derived prostaglandins in ovulation and implantation. Biol. Rerpod. 2001, 64, 1557–1565. [Google Scholar] [CrossRef]
  78. Ben-Ami, I.; Freimann, S.; Armon, L.; Dantes, A.; Strassburger, D.; Friedler, S.; Raziel, A.; Seger, R.; Ron-El, R.; Amsterdam, A. PGE2 up-regulates EGF-like growth factor biosynthesis in human granulosa cells: New insights into the coordination between PGE2 and LH in ovulation. Mol. Hum. Reprod. 2006, 12, 593–599. [Google Scholar] [CrossRef] [PubMed]
  79. Park, J.Y.; Su, Y.Q.; Ariga, M.; Law, E.; Jin, S.L.; Conti, M. EGF-like growth factors as mediators of LH action in the ovulatory follicle. Science 2004, 303, 682–684. [Google Scholar] [CrossRef] [PubMed]
  80. Hsieh, M.; Lee, D.; Panigone, S.; Horner, K.; Chen, R.; Theologis, A.; Lee, D.C.; Threadgill, D.W.; Conti, M. Luteinizing hormone-dependent activation of the epidermal growth factor network is essential for ovulation. Mol. Cell. Biol. 2007, 27, 1914–1924. [Google Scholar] [CrossRef] [PubMed]
  81. Goldberg, A.L.; Stein, R.; Adams, J. New insights into proteasome function: From archaebacteria to drug development. Chem. Biol. 1995, 2, 503–508. [Google Scholar] [CrossRef]
  82. Coux, O.; Tanaka, K.; Goldberg, A.L. Structure and functions of the 20S and 26S proteasomes. Annu. Rev. Biochem. 1996, 65, 801–847. [Google Scholar] [CrossRef] [PubMed]
  83. Josefsberg, L.B.; Galiani, D.; Dantes, A.; Amsterdam, A.; Dekel, N. The proteasome is involved in the first metaphase-to-anaphase transition of meiosis in rat oocytes. Biol. Reprod. 2000, 62, 1270–1277. [Google Scholar] [CrossRef] [PubMed]
  84. Lee, D.H.; Goldberg, A.L. Proteasome inhibitors: Valuable new tools for cell biologists. Trends Cell Biol. 1998, 8, 397–403. [Google Scholar] [CrossRef]
  85. Rock, K.L.; Gramm, C.; Rothstein, L.; Clark, K.; Stein, R.; Dick, L.; Hwang, D.; Goldberg, A.L. Inhibitors of the proteasome block the degradation of most cell proteins and the generetaion of peptides presented on MHC class I molecules. Cell 1994, 78, 767–771. [Google Scholar] [CrossRef]
  86. Huo, L.J.; Fan, H.Y.; Liang, C.G.; Yu, L.Z.; Zhong, Z.S.; Chen, D.Y.; Sun, Q.Y. Regulation of ubiquitin-proteasome pathway on pig oocyte meiotic maturation and fertilization. Biol. Reprod. 2004, 71, 853–862. [Google Scholar] [CrossRef] [PubMed]
  87. Huo, L.J.; Fan, H.Y.; Zhong, Z.S.; Chen, D.Y.; Schatten, H.; Sun, Q.Y. Ubiquitin-proteasome pathway modulates mouse oocyte meiotic maturation and fertilization via regulation of MAPK cascade and cyclin B1 degradation. Mech. Dev. 2004, 121, 1275–1287. [Google Scholar] [CrossRef] [PubMed]
  88. Chmelikova, E.; Sedmikova, M.; Rajmon, R.; Petr, J.; Svestkova, D.; Jilek, F. Effect of proteasome inhibitor MG132 on in vitro maturation of pig oocytes. Zygote 2004, 12, 157–162. [Google Scholar] [CrossRef] [PubMed]
  89. Yi, Y.J.; Nagyova, E.; Manandhar, G.; Prochazka, R.; Sutovsky, M.; Park, C.S.; Sutovsky, P. Proteolytic activity of the 26S proteasome is required for the meiotic resumption, germinal vesicle breakdown, and cumulus expansion of porcine cumulus-oocyte complexes matured in vitro. Biol. Reprod. 2008, 78, 115–126. [Google Scholar] [CrossRef] [PubMed]
  90. Mailhes, J.B.; Hilliard, C.; Lowery, M.; London, S.N. MG-132, an inhibitor of proteasomes and calpains, induced inhibition of oocyte maturation and aneuploidy in mouse oocytes. Cell Chromosom. 2002, 1, 2–7. [Google Scholar] [CrossRef]
  91. Rugg, M.S.; Willis, A.C.; Mukhopadhyay, D.; Hascall, V.C.; Fries, E.; Fülöp, C.; Milner, C.M.; Day, A.J. Characterization of complexes formed between TSG-6 and inter-α-inhibitor that act as intermediates in the covalent transfer of heavy chains onto hyaluronan. J. Biol. Chem. 2005, 280, 25674–25686. [Google Scholar] [CrossRef] [PubMed]
  92. Nagyova, E.; Scsukova, S.; Nemcova, L.; Mlynarcikova, A.; Yi, Y.-J.; Sutovsky, M.; Sutovsky, P. Inhibition of proteasomal proteolysis affects expression of extracellular matrix components and steroidogenesis in porcine oocyte-cumulus complexes. Domest. Anim. Endocrinol. 2012, 42, 50–62. [Google Scholar] [CrossRef] [PubMed]
  93. Tsafriri, A.; Cao, X.; Ashkenazi, H.; Motola, S.; Popliker, M.; Pomerantz, S.H. Resumption of oocyte meiosis in mammals: On models, meiosis activating sterols, steroids and EGF-like factors. Mol. Cell. Endocrinol. 2005, 234, 37–45. [Google Scholar] [CrossRef] [PubMed]
  94. Sutovsky, P.; Flechon, J.E.; Flechon, B.; Motlik, J.; Peynot, N.; Chesne, P.; Heyman, Y. Dynamic changes of gap junctions and cytoskeleton during in vitro culture of cattle oocyte cumulus complexes. Biol. Reprod. 1993, 49, 1277–1287. [Google Scholar] [CrossRef] [PubMed]
  95. Luciano, A.M.; Lodde, V.; Beretta, M.S.; Colleoni, S.; Lauria, A.; Modina, S. Developmental capability of denuded bovine oocyte in co-culture system with intact cumulus-oocyte complexes; role of cumulus cells, cyclic adenosine-3′,5′-monophosphate, and glutathione. Mol. Reprod. Dev. 2005, 71, 389–397. [Google Scholar] [CrossRef] [PubMed]
  96. Gutnisky, C.; Dalvit, G.C.; Pintos, L.N.; Thompson, J.G.; Beconi, M.T.; Cetica, P.D. Influence of hyaluronic acid synthesis and cumulus mucification on bovine oocyte in vitro maturation, fertilization and embryo development. Reprod. Fertil. Dev. 2007, 19, 488–497. [Google Scholar] [CrossRef] [PubMed]
  97. Nuttinck, F.; Marquant-LeGuienne, B.; Clement, L.; Reinaud, P.; Charpigny, G.; Grimard, B. Expression of genes involved in prostaglandin E2 and progesterone production in bovine cumulu-oocyte complex during in vitro maturation and fertilization. Reproduction 2008, 135, 593–603. [Google Scholar] [CrossRef] [PubMed]
  98. Iwamasa, J.; Shibata, S.; Tanaka, N.; Matsuura, K.; Okamura, H. The relationship between ovarian progesterone and proteolytic enzyme activity during ovulation in the gonadotropin-treated immature rat. Biol. Reprod. 1992, 46, 309–313. [Google Scholar] [CrossRef] [PubMed]
  99. Jezova, M.; Scsukova, S.; Nagyova, E.; Vranova, J.; Prochazka, R.; Kolena, J. Effect of intraovarian factors on porcine follicular cells: Cumulus expansion, granulosa and cumulus cell progesterone production. Anim. Reprod. Sci. 2001, 65, 115–126. [Google Scholar] [CrossRef]
  100. Shimada, M.; Terada, T. FSH and LH induce progesterone production and progesterone receptor synthesis in cumulus cells, a requirement for meiotic resumption in porcine oocytes. Mol. Hum. Reprod. 2002, 8, 612–618. [Google Scholar] [CrossRef] [PubMed]
  101. Granot, Z.; Melamed-Book, N.; Bahat, A.; Orly, J. Turnover of STAR protein: Roles for the proteasome and mitochondrial proteases. Mol. Cell. Endocrinol. 2007, 265–266, 51–58. [Google Scholar] [CrossRef] [PubMed]
  102. Tajima, K.; Babich, S.; Yoshida, Y.; Dantes, A.; Strauss, J.F., 3rd; Amsterdam, A. The proteasome inhibitor MG132 promotes accumulation of the steroidogenic acute regulatory protein (star) and steroidogenesis. FEBS Lett. 2001, 490, 59–64. [Google Scholar] [CrossRef]
  103. Ziolkowska, A.; Tortorella, C.; Nussdorfer, G.G.; Rucinski, M.; Majchrzak, M.; Malendowicz, L.K. Accumulation of steroidogenic acute regulatory protein mRNA, and decrease in the secretory and proliferative activity of rat adrenocortical cells in the presence of proteasome inhibitors. Int. J. Mol. Med. 2006, 17, 865–868. [Google Scholar] [CrossRef] [PubMed]
  104. Clark, B.J.; Wells, J.; King, S.R.; Stocco, D.M. The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J. Biol. Chem. 1994, 269, 28314–28322. [Google Scholar] [PubMed]
Table 1. Gonadotropin-induced matrix components essential for the formation and stability of the HA-rich oocyte-cumulus ECM.
Table 1. Gonadotropin-induced matrix components essential for the formation and stability of the HA-rich oocyte-cumulus ECM.
ECM ComponentDescriptionTissue Location
(Oocyte-Cumulus Complexes-OCC)
SpeciesReferences
HAHyaluronanOCCMice[15,16,17,18]
OCCPigs[19]
IαIInter-alpha-trypsin inhibitor (also called inter-alpha-trypsin inhibitor (ITI))OCCMice[10,18,20,21]
OCCPigs[12,22]
TNFAIP6Tumor necrosis factor alpha-induced protein 6 (also called Tumor necrosis factor stimulated gene-6 (TSG-6))OCCMice[13,18,23,24]
OvaryRats[25]
OCCPigs[26,27]
Ovarian folliclesEquine[28]
PTX3Pentraxin 3OCCMice[29,30,31,32,33]
OCCPigs[34]

Share and Cite

MDPI and ACS Style

Nagyova, E. The Biological Role of Hyaluronan-Rich Oocyte-Cumulus Extracellular Matrix in Female Reproduction. Int. J. Mol. Sci. 2018, 19, 283. https://doi.org/10.3390/ijms19010283

AMA Style

Nagyova E. The Biological Role of Hyaluronan-Rich Oocyte-Cumulus Extracellular Matrix in Female Reproduction. International Journal of Molecular Sciences. 2018; 19(1):283. https://doi.org/10.3390/ijms19010283

Chicago/Turabian Style

Nagyova, Eva. 2018. "The Biological Role of Hyaluronan-Rich Oocyte-Cumulus Extracellular Matrix in Female Reproduction" International Journal of Molecular Sciences 19, no. 1: 283. https://doi.org/10.3390/ijms19010283

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop