Growth differentiation factor 8 suppresses cell proliferation by up-regulating CTGF expression in human granulosa cells

Chang, Hsun‐Ming; Pan, Hui-Hui; Cheng, Jung‐Chien; Zhu, Yimin; Leung, Peter C. K.

doi:10.1016/j.mce.2015.11.009

Cited by 39 publications

(22 citation statements)

References 47 publications

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“…Moreover, the present study found that myostatin increased viable cell number in both TC and GC cultures suggesting a positive effect on cell proliferation and/or survival. This finding contrasts with a report that myostatin reduces proliferation of human granulosa-lutein cells, evidently by upregulating connective tissue growth factor expression (Chang et al 2016b). The reason for this discrepancy is not known but may reflect the effect of luteinisation or a species difference.…”

Section: Cyp19a1contrasting

confidence: 92%

“…For instance, treatment of human granulosa-lutein cells with myostatin downregulated expression of steroidogenic acute regulatory protein (STAR) and reduced progesterone secretion, whilst increasing cytochrome P450 aromatase (CYP19A1) expression, FSHR expression and oestradiol secretion (Chang et al 2015, 2016a). An anti-proliferative effect of myostatin on human granulosa-lutein cells was also reported (Chang et al 2016b). To our knowledge, there have been no reports on effects of myostatin on non-luteinised granulosa cells, nor on theca cells from any species.…”

Section: Introductionmentioning

confidence: 75%

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Myostatin is expressed in bovine ovarian follicles and modulates granulosal and thecal steroidogenesis

et al. 2018

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Myostatin plays a negative role in skeletal muscle growth regulation but its potential role in the ovary has received little attention. Here, we first examined relative expression of myostatin (MSTN), myostatin receptors (ACVR1B, ACVR2B and TGFBR1) and binding protein, follistatin (FST), in granulosa (GC) and theca (TC) cells of developing bovine follicles. Secondly, using primary GC and TC cultures, we investigated whether myostatin affects steroidogenesis and cell number. Thirdly, effects of gonadotropins and other factors on MSTN expression in GC and TC were examined. MSTN, ACVR1B, TGFBR1, ACVR2B and FST mRNA was detected in both GC and TC at all follicle stages. Immunohistochemistry confirmed follicular expression of myostatin protein. Interestingly, MSTN mRNA expression was lowest in GC of large estrogen-active follicles while GC FST expression was maximal at this stage. In GC, myostatin increased basal CYP19A1 expression and estradiol secretion whilst decreasing basal and FSH-induced HSD3B1 expression and progesterone secretion and increasing cell number. Myostatin also reduced IGF-induced progesterone secretion. FSH and dihydrotestosterone had no effect on granulosal MSTN expression whilst insulin-like growth factor and tumour necrosis factor-alpha suppressed MSTN level. In TC, myostatin suppressed basal and LH-stimulated androgen secretion in a follistatin-reversible manner and increased cell number, without affecting progesterone secretion. LH reduced thecal MSTN expression whilst BMP6 had no effect. Collectively, results indicate that, in addition to being potentially responsive to muscle-derived myostatin from the circulation, myostatin may have an intra-ovarian autocrine/paracrine role to modulate thecal and granulosal steroidogenesis and cell proliferation/survival.

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Section: Cyp19a1contrasting

confidence: 92%

Section: Introductionmentioning

confidence: 75%

Myostatin is expressed in bovine ovarian follicles and modulates granulosal and thecal steroidogenesis

et al. 2018

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“…At the periovulatory stage, various regulatory endocrine and paracrine factors meticulously modulate the functional switch of GCs from a highly proliferative status to a non-proliferative, terminally differentiated status (McGee and Hsueh, 2000). Beyond its role in regulating steroid production, an in vitro study showed that GDF8 suppresses human GC proliferation (Chang et al ., 2016). This negative regulatory effect is mediated by another growth factor, connective tissue growth factor (CTGF), indicating that GDF8 and CTGF may be involved in the control of highly proliferative and non-proliferative events during human follicular development (Chang et al ., 2016).…”

Section: Novel Role Of Gdf8 In the Human Ovarymentioning

confidence: 99%

“…Beyond its role in regulating steroid production, an in vitro study showed that GDF8 suppresses human GC proliferation (Chang et al ., 2016). This negative regulatory effect is mediated by another growth factor, connective tissue growth factor (CTGF), indicating that GDF8 and CTGF may be involved in the control of highly proliferative and non-proliferative events during human follicular development (Chang et al ., 2016). …”

Section: Novel Role Of Gdf8 In the Human Ovarymentioning

confidence: 99%

Oocyte–somatic cell interactions in the human ovary—novel role of bone morphogenetic proteins and growth differentiation factors

Chang

Qiao

Leung

2016

Hum. Reprod. Update

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226

207

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BACKGROUNDInitially identified for their capability to induce heterotopic bone formation, bone morphogenetic proteins (BMPs) are multifunctional growth factors that belong to the transforming growth factor β superfamily. Using cellular and molecular genetic approaches, recent studies have implicated intra-ovarian BMPs as potent regulators of ovarian follicular function. The bi-directional communication of oocytes and the surrounding somatic cells is mandatory for normal follicle development and oocyte maturation. This review summarizes the current knowledge on the physiological role and molecular determinants of these ovarian regulatory factors within the human germline-somatic regulatory loop.OBJECTIVE AND RATIONALEThe regulation of ovarian function remains poorly characterized in humans because, while the fundamental process of follicular development and oocyte maturation is highly similar across species, most information on the regulation of ovarian function is obtained from studies using rodent models. Thus, this review focuses on the studies that used human biological materials to gain knowledge about human ovarian biology and disorders and to develop strategies for preventing, diagnosing and treating these abnormalities.SEARCH METHODSRelevant English-language publications describing the roles of BMPs or growth differentiation factors (GDFs) in human ovarian biology and phenotypes were comprehensively searched using PubMed and the Google Scholar database. The publications included those published since the initial identification of BMPs in the mammalian ovary in 1999 through July 2016.OUTCOMESStudies using human biological materials have revealed the expression of BMPs, GDFs and their putative receptors as well as their molecular signaling in the fundamental cells (oocyte, cumulus/granulosa cells (GCs) and theca/stroma cells) of the ovarian follicles throughout follicle development. With the availability of recombinant human BMPs/GDFs and the development of immortalized human cell lines, functional studies have demonstrated the physiological role of intra-ovarian BMPs/GDFs in all aspects of ovarian functions, from follicle development to steroidogenesis, cell–cell communication, oocyte maturation, ovulation and luteal function. Furthermore, there is crosstalk between these potent ovarian regulators and the endocrine signaling system. Dysregulation or naturally occurring mutations within the BMP system may lead to several female reproductive diseases. The latest development of recombinant BMPs, synthetic BMP inhibitors, gene therapy and tools for BMP-ligand sequestration has made the BMP pathway a potential therapeutic target in certain human fertility disorders; however, further clinical trials are needed. Recent studies have indicated that GDF8 is an intra-ovarian factor that may play a novel role in regulating ovarian functions in the human ovary.WIDER IMPLICATIONSIntra-ovarian BMPs/GDFs are critical regulators of folliculogenesis and human ovarian functions. Any dysregulation or variations in these ligand...

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“…It has been well characterized that GDF-8 is a critical autocrine/paracrine inhibitor of skeletal muscle growth and differentiation 11 12 13 . Interestingly, GDF-8 is also expressed in the human reproductive system, such as in granulosa cells, follicular fluid and trophoblasts 14 15 16 17 . In addition, recently, our group has revealed some novel biological functions of GDF-8 in regulation of human cumulus expansion and steroidogenesis 15 16 .…”

mentioning

confidence: 99%

Serum GDF-8 levels change dynamically during controlled ovarian hyperstimulation in patients undergoing IVF/ICSI-ET

Fang

Zhang

et al. 2016

Sci Rep

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Growth differentiation factor-8 (GDF-8) is found in the human serum, follicular fluid and granulosa cells. Our previous studies have shown that the human cumulus expansion and steroidogenesis can be regulated by GDF-8. However, thus far, the expression profile of GDF-8 in serum and whether the level of serum GDF-8 influences pregnancy results for patients treated with in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) is totally unknown. In this study, we showed that GDF-8 had a dynamic trend during controlled ovarian hyperstimulation (COH) procedure. On human chorionic gonadotropin (hCG) administration day, patients with a GDF-8 level higher than 4.7 ng/ml had lower progesterone levels and a higher pregnancy rate. From hCG day to oocyte pick-up day, patients with a GDF-8 decrease greater than 1.3 ng/ml had a higher progesterone increase and a higher pregnancy rate. Importantly, the levels of GDF-8 were negatively correlated with progesterone levels. Our findings provide evidences that GDF-8 plays an important role in ensuring successful pregnancy by regulating progesterone levels.

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Growth differentiation factor 8 suppresses cell proliferation by up-regulating CTGF expression in human granulosa cells

Cited by 39 publications

References 47 publications

Myostatin is expressed in bovine ovarian follicles and modulates granulosal and thecal steroidogenesis

Myostatin is expressed in bovine ovarian follicles and modulates granulosal and thecal steroidogenesis

Oocyte–somatic cell interactions in the human ovary—novel role of bone morphogenetic proteins and growth differentiation factors

Serum GDF-8 levels change dynamically during controlled ovarian hyperstimulation in patients undergoing IVF/ICSI-ET

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