Regulation of Bone Morphogenetic Protein 15 on Follicular Development and Its Relationship with Reproductive Endocrine Diseases

doi:10.12280/gjszjk.20220023

Abstract

Abstract:

Bone morphogenetic protein 15 (BMP15) as an oocyte-secreted factor is vital to the regulation of follicle development. BMP15 promotes the development and maturation of oocytes by cooperating with amphiregulin and up-regulating the expression of cumulus expansion genes. BMP15 also promotes the proliferation and differentiation of granulosa cells by increasing the sensitivity of granulosa cells to FSH and stimulating the expression of Kit ligands in granulosa cells. BMP15 inhibits follicular atresia by regulating the expression of follicle apoptosis-related factors; and BMP15 can also mediate the regulation of steroid hormones by regulating the FSH receptor and the downstream Smad signaling pathways. The decreased expression or gene mutation of BMP15 may induce the apoptosis of granulosa cells, hinder the process of early follicle development and oogenesis, and mediate the pathogenesis of various diseases such as polycystic ovary syndrome and premature ovarian insufficiency. In this article, we review the roles of BMP15 in folliculogenesis and the research progress of BMP15-related reproductive endocrine diseases.

Key words: Bone morphogenetic proteins, Follicular atresia, Granulosa cells, Apoptosis, Polycystic ovary syndrome, Premature ovarian insufficiency

CHEN Ming-li, ZHAO Xiao-li, FENG Wei-hua, XIA Tian. Regulation of Bone Morphogenetic Protein 15 on Follicular Development and Its Relationship with Reproductive Endocrine Diseases[J]. Journal of International Reproductive Health/Family Planning, 2022, 41(3): 252-257.

References 36

[1]	Cui X, Jing X, Wu X, et al. Abnormal expression levels of BMP15/Smad1 are associated with granulosa cell apoptosis in patients with polycystic ovary syndrome[J]. Mol Med Rep, 2017, 16(6):8231-8236. doi: 10.3892/mmr.2017.7658. doi: 10.3892/mmr.2017.7658 URL
[2]	Chu YL, Xu YR, Yang WX, et al. The role of FSH and TGF-β superfamily in follicle atresia[J]. Aging(Albany NY), 2018, 10(3):305-321. doi: 10.18632/aging.101391. doi: 10.18632/aging.101391
[3]	Chang HM, Qiao J, Leung PC. Oocyte-somatic cell interactions in the human ovary-novel role of bone morphogenetic proteins and growth differentiation factors[J]. Hum Reprod Update, 2016, 23(1):1-18. doi: 10.1093/humupd/dmw039. doi: 10.1093/humupd/dmw039 URL
[4]	Persani L, Rossetti R, Di Pasquale E, et al. The fundamental role of bone morphogenetic protein 15 in ovarian function and its involvement in female fertility disorders[J]. Hum Reprod Update, 2014, 20(6):869-883. doi: 10.1093/humupd/dmu036. doi: 10.1093/humupd/dmu036 pmid: 24980253
[5]	Mottershead DG, Sugimura S, Al-Musawi SL, et al. Cumulin, an Oocyte-secreted Heterodimer of the Transforming Growth Factor-β Family, Is a Potent Activator of Granulosa Cells and Improves Oocyte Quality[J]. J Biol Chem, 2015, 290(39):24007-24020. doi: 10.1074/jbc.M115.671487. doi: 10.1074/jbc.M115.671487 pmid: 26254468
[6]	Margulis S, Abir R, Felz C, et al. Bone morphogenetic protein 15 expression in human ovaries from fetuses, girls, and women[J]. Fertil Steril, 2009, 92(5):1666-1673. doi: 10.1016/j.fertnstert.2008.08.119. doi: 10.1016/j.fertnstert.2008.08.119 pmid: 18980767
[7]	Hussein TS, Thompson JG, Gilchrist RB. Oocyte-secreted factors enhance oocyte developmental competence[J]. Dev Biol, 2006, 296(2):514-521. doi: 10.1016/j.ydbio.2006.06.026. doi: 10.1016/j.ydbio.2006.06.026 pmid: 16854407
[8]	Velásquez A, Mellisho E, Castro FO, et al. Effect of BMP15 and/or AMH during in vitro maturation of oocytes from involuntarily culled dairy cows[J]. Mol Reprod Dev, 2019, 86(2):209-223. doi: 10.1002/mrd.23096. doi: 10.1002/mrd.23096 URL
[9]	Delgado JC, Hamilton T, Mendes CM, et al. Bone morphogenetic protein 15 supplementation enhances cumulus expansion, nuclear maturation and progesterone production of in vitro-matured bovine cumulus-oocyte complexes[J]. Reprod Domest Anim, 2021, 56(5):754-763. doi: 10.1111/rda.13914. doi: 10.1111/rda.13914 URL
[10]	Dey SR, Deb GK, Ha AN, et al. Coculturing denuded oocytes during the in vitro maturation of bovine cumulus oocyte complexes exerts a synergistic effect on embryo development[J]. Theriogenology, 2012, 77(6):1064-1077. doi: 10.1016/j.theriogenology.2011.10.009. doi: 10.1016/j.theriogenology.2011.10.009 pmid: 22153275
[11]	Sugimura S, Ritter LJ, Sutton-McDowall ML, et al. Amphiregulin co-operates with bone morphogenetic protein 15 to increase bovine oocyte developmental competence: effects on gap junction-mediated metabolite supply[J]. Mol Hum Reprod, 2014, 20(6):499-513. doi: 10.1093/molehr/gau013. doi: 10.1093/molehr/gau013 pmid: 24557840
[12]	Sugimura S, Ritter LJ, Rose RD, et al. Promotion of EGF receptor signaling improves the quality of low developmental competence oocytes[J]. Dev Biol, 2015, 403(2):139-149. doi: 10.1016/j.ydbio.2015.05.008. doi: 10.1016/j.ydbio.2015.05.008 pmid: 25981108
[13]	Sirait B, Wiweko B, Jusuf AA, et al. Oocyte Competence Biomarkers Associated With Oocyte Maturation: A Review[J]. Front Cell Dev Biol, 2021, 9:710292. doi: 10.3389/fcell.2021.710292. doi: 10.3389/fcell.2021.710292 URL
[14]	Moore RK, Otsuka F, Shimasaki S. Molecular basis of bone morphogenetic protein-15 signaling in granulosa cells[J]. J Biol Chem, 2003, 278(1):304-310. doi: 10.1074/jbc.M207362200. doi: 10.1074/jbc.M207362200 URL
[15]	Shimizu K, Nakamura T, Bayasula, et al. Molecular mechanism of FSHR expression induced by BMP15 in human granulosa cells[J]. J Assist Reprod Genet, 2019, 36(6):1185-1194. doi: 10.1007/s10815-019-01469-y. doi: 10.1007/s10815-019-01469-y URL
[16]	Otsuka F, Shimasaki S. A negative feedback system between oocyte bone morphogenetic protein 15 and granulosa cell kit ligand: its role in regulating granulosa cell mitosis[J]. Proc Natl Acad Sci U S A, 2002, 99(12):8060-8065. doi: 10.1073/pnas.122066899. doi: 10.1073/pnas.122066899 pmid: 12048244
[17]	Hussein TS, Froiland DA, Amato F, et al. Oocytes prevent cumulus cell apoptosis by maintaining a morphogenic paracrine gradient of bone morphogenetic proteins[J]. J Cell Sci, 2005, 118(Pt 22):5257-5268. doi: 10.1242/jcs.02644. doi: 10.1242/jcs.02644 pmid: 16263764
[18]	Zhai B, Liu H, Li X, BMP15 prevents cumulus cell apoptosis through CCL2 and FBN1 in porcine ovaries[J]. Cell Physiol Biochem, 2013, 32(2):264-278. doi: 10.1159/000354435. doi: 10.1159/000354435 pmid: 23942191
[19]	Yao W, Wang S, Du X, et al. SMAD4 Inhibits Granulosa Cell Apoptosis via the miR-183-96-182 Cluster and FoxO1 Axis[J]. Reprod Sci, 2022, 29(5):1577-1585. doi: 10.1007/s43032-021-00690-4. doi: 10.1007/s43032-021-00690-4 URL
[20]	Lawrenz B, Melado L, Fatemi H. Premature progesterone rise in ART-cycles[J]. Reprod Biol, 2018, 18(1):1-4. doi: 10.1016/j.repbio.2018.01.001. doi: 10.1016/j.repbio.2018.01.001
[21]	Otsuka F, Yamamoto S, Erickson GF, et al. Bone morphogenetic protein-15 inhibits follicle-stimulating hormone (FSH) action by suppressing FSH receptor expression[J]. J Biol Chem, 2001, 276(14):11387-11392. doi: 10.1074/jbc.M010043200. doi: 10.1074/jbc.M010043200 pmid: 11154695
[22]	Chang HM, Cheng JC, Klausen C, et al. BMP15 suppresses progesterone production by down-regulating StAR via ALK3 in human granulosa cells[J]. Mol Endocrinol, 2013, 27(12):2093-2104. doi: 10.1210/me.2013-1233. doi: 10.1210/me.2013-1233 URL
[23]	Wang W, Chen X, Li X, et al. Interference RNA-based silencing of endogenous SMAD4 in porcine granulosa cells resulted in decreased FSH-mediated granulosa cells proliferation and steroidogenesis[J]. Reproduction, 2011, 141(5):643-651. doi: 10.1530/REP-10-0098. doi: 10.1530/REP-10-0098 pmid: 21292728
[24]	Risal S, Pei Y, Lu H, et al. Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome[J]. Nat Med, 2019, 25(12):1894-1904. doi: 10.1038/s41591-019-0666-1. doi: 10.1038/s41591-019-0666-1 URL
[25]	Yang D, Li N, Ma A, et al. Identification of Potential Biomarkers of Polycystic Ovary Syndrome via Integrated Bioinformatics Analysis[J]. Reprod Sci, 2021, 28(5):1353-1361. doi: 10.1007/s43032-020-00352-x. doi: 10.1007/s43032-020-00352-x URL
[26]	Wei LN, Huang R, Li LL, et al. Reduced and delayed expression of GDF9 and BMP15 in ovarian tissues from women with polycystic ovary syndrome[J]. J Assist Reprod Genet, 2014, 31(11):1483-1490. doi: 10.1007/s10815-014-0319-8. doi: 10.1007/s10815-014-0319-8 URL
[27]	Liu J, Wang B, Wei Z, et al. Mutational analysis of human bone morphogenetic protein 15 in Chinese women with polycystic ovary syndrome[J]. Metabolism, 2011, 60(11):1511-1514. doi: 10.1016/j.metabol.2010.10.006. doi: 10.1016/j.metabol.2010.10.006 URL
[28]	Mehdizadeh A, Sheikhha MH, Kalantar SM, et al. Mutation analysis of exon1 of bone morphogenetic protein-15 gene in Iranian patients with polycystic ovarian syndrome[J]. Int J Reprod Biomed, 2016, 14(8):527-532. pmid: 27679828
[29]	Belli M, Shimasaki S. Molecular Aspects and Clinical Relevance of GDF9 and BMP15 in Ovarian Function[J]. Vitam Horm, 2018, 107:317-348. doi: 10.1016/bs.vh.2017.12.003. doi: 10.1016/bs.vh.2017.12.003
[30]	Qin Y, Tang T, Li W, et al. Bone Morphogenetic Protein 15 Knockdown Inhibits Porcine Ovarian Follicular Development and Ovulation[J]. Front Cell Dev Biol, 2019, 7:286. doi: 10.3389/fcell.2019.00286. doi: 10.3389/fcell.2019.00286 URL
[31]	Di Pasquale E, Beck-Peccoz P, Persani L. Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene[J]. Am J Hum Genet, 2004, 75(1):106-111. doi: 10.1086/422103. doi: 10.1086/422103 pmid: 15136966
[32]	Rossetti R, Ferrari I, Bestetti I, et al. Fundamental role of BMP15 in human ovarian folliculogenesis revealed by null and missense mutations associated with primary ovarian insufficiency[J]. Hum Mutat, 2020, 41(5):983-997. doi: 10.1002/humu.23988. doi: 10.1002/humu.23988 URL
[33]	Afkhami F, Shahbazi S, Farzadi L, et al. Novel bone morphogenetic protein 15 (BMP15) gene variants implicated in premature ovarian insufficiency[J]. Reprod Biol Endocrinol, 2022, 20(1):42. doi: 10.1186/s12958-022-00913-6. doi: 10.1186/s12958-022-00913-6
[34]	Ferrarini E, De Marco G, Orsolini F, et al. Characterization of a novel mutation V136L in bone morphogenetic protein 15 identified in a woman affected by POI[J]. J Ovarian Res, 2021, 14(1):85. doi: 10.1186/s13048-021-00836-7. doi: 10.1186/s13048-021-00836-7 pmid: 34187539
[35]	Santos M, Cordts EB, Peluso C, et al. Association of BMP15 and GDF9 variants to premature ovarian insufficiency[J]. J Assist Reprod Genet, 2019, 36(10):2163-2169. doi: 10.1007/s10815-019-01548-0. doi: 10.1007/s10815-019-01548-0 URL
[36]	Park MJ, Ahn JW, Kim KH, et al. Prediction of ovarian aging using ovarian expression of BMP15, GDF9, and C-KIT[J]. Exp Biol Med(Maywood), 2020, 245(8):711-719. doi: 10.1177/1535370220915826. doi: 10.1177/1535370220915826