BMP2 is a member of the transforming growth factor-beta (TGFB) superfamily of ligands.
NCBI Summary:
This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer, which plays a role in bone and cartilage development. Duplication of a regulatory region downstream of this gene causes a form of brachydactyly characterized by a malformed index finger and second toe in human patients. [provided by RefSeq, Jul 2016]
General function
Ligand, Hormone, Growth factor
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Cellular localization
Secreted
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Ovarian function
Follicle endowment, Steroid metabolism
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Bone morphogenetic protein 2 upregulates SERPINE2 expression through noncanonical SMAD2/3 and p38 MAPK signaling pathways in human granulosa-lutein cells. Luo X et al. (2021) Serine protease inhibitor-E2 (SERPINE2) is highly expressed in the granulosa cells of growing follicles and the dynamic changes in SERPINE2 expression are correlated with follicular development and ovulation in several mammals, including mice, cattle, sheep, and humans. Bone morphogenetic proteins (BMPs) and their functional receptors are extensively expressed in the ovary and play critical roles in the regulation of ovarian folliculogenesis and luteal function. To date, whether BMPs regulate the expression of SERPINE2 during human follicular development remains to be elucidated. The aim of this study was to investigate the effects of BMPs on the regulation of SERPINE2 expression (a major regulator of plasminogen activators PA]) and the underlying mechanisms using primary and immortalized human granulosa-lutein (hGL) cells. Our results demonstrated that these BMPs (BMP2, BMP4, BMP6, BMP7, and BMP15) induced differential upregulation of SERPINE2 expression. In this regard, BMP2 is the major modulator that has the best cellular activity, which further decreased the production of urokinase PA and tissue PA in hGL cells. In addition to canonical SMAD1/5/8 signaling, BMP2 also activates noncanonical SMAD2/3 and p38 mitogen-activated protein kinase (MAPK) signaling. Using two inhibition approaches (kinase receptor inhibitors and siRNA-mediated knockdown), we found that SMAD2/3-SMAD4 and p38 MAPK, but not SMAD1/5/8 signaling, was involved in the BMP2-induced upregulation of SERPINE2 expression via activin receptor-like kinase 3. These findings deepen our understanding of the differential effect of BMPs in regulating follicular function and provide new insights of the molecular mechanisms by which BMP2 regulates the expression of SERPINE2 in human granulosa cells.//////////////////Stimulation of primordial follicle assembly by estradiol-17β requires the action of bone morphogenetic protein-2 (BMP2). [Chakraborty P et al. (2017) Primordial follicle (PF) pool determines the availability of follicles for ovulation in all mammals. Premature depletion of the PF reserve leads to subfertility or infertility. Bone morphogenetic protein 2 (BMP2) promotes PF formation by facilitating oocyte and granulosa cell development. Estradiol-17β (E2) upregulates PF formation in developing hamster ovaries. However, if BMP2 mediates E2 effect is not known. We hypothesize that E2 facilitates the effect of BMP2 on somatic to granulosa cell transition. BMP2 and E2 together significantly upregulated the percentage of PFs in hamster fetal ovaries in vitro compared with either of the treatments alone. E2 also promoted BMP2 expression in vivo. Inhibition of BMP2 receptors suppressed E2-stimulation of PF formation while knockdown of BMP2 in vitro significantly suppressed the E2 effect. In contrast, estrogen receptor blocker did not affect BMP2 action. Inhibition of the activity of E2 or BMP2 receptors, either alone or combined during the last two days of the culture (C6-C8) resulted in a significant decrease in PF formation by C8, suggesting that both BMP2 and E2 action is essential for somatic cell differentiation for PF formation. Together, the results suggest that E2 activates BMP2-BMPR system leading to the formation of primordial follicles.//////////////////
Bone morphogenetic protein two regulates cell-cell communication by down-regulating connexin43 expression in luteinized human granulosa cells. Wu YT et al. (2016) Does bone morphogenetic protein 2 (BMP2) regulate connexin43 (Cx43) and modulate cell-cell communication in luteinized human granulosa cells? BMP2 decreases gap junction intercellular communication (GJIC) of luteinized human granulosa cells by down-regulating Cx43 expression through an activin receptor-like kinase (ALK)2/ALK3-mediated Sma- and Mad-related protein (SMAD)-dependent signaling pathway. BMP2 and its putative receptors are highly expressed in the human corpus luteum and are involved in the process of luteolysis. Cx43-coupled gap junctions play a critical role in the development and maintenance of corpus luteum. This is a laboratory study conducted over a 1-year period. At least three independent experiments with three replicates were conducted and the experimental samples were compared with the appropriate vehicle controls for all of the inhibition-approach, concentration-dependent or time-course studies. SVOG cell line (immortalized human granulosa-lutein cells derived from in vitro fertilization patients in an academic research center) was used as the study model. The changes of Cx43 expression and levels of phosphorylated SMAD1/5/8 protein were evaluated after exposure to recombinant human BMP2. Real-time quantitative PCR and Western blot analysis were used to examine the specific mRNA and protein levels, respectively. The BMP/TGF-β type I receptor inhibitors (Dorsomorphin, DMH-1 and SB431542) and target depletion small interfering RNAs (ALK2, ALK3, ALK6 and SMAD4) were used to investigate the underlying molecular mechanisms. A scrape loading and dye transfer assay was used to evaluate the GJIC between the SVOG cells. Treatment with BMP2 down-regulated the expression of Cx43 and decreased the GJIC activity, whereas it increased the phosphorylated SMAD1/5/8 protein in SVOG cells (P < 0.05). These biological effects were abolished by pre-treatment with the BMP type I receptor inhibitors, Dorsomorphin and DMH-1 (P < 0.05), but not SB431542. Additionally, the individual or concomitant small interfering RNA-mediated knockdown of ALK2 and ALK3, but not ALK6 attenuated the BMP2-induced increases in phosphorylated SMAD1/5/8 and down-regulation of Cx43 expression (P < 0.05). The knockdown of SMAD4 completely abolished the BMP2-induced down-regulation of Cx43 expression (P < 0.05). This experimental study was conducted in an in vitro cell culture system, and may not reflect a realistic intra-ovarian environment. Our results suggested that BMP2 may be involved in the local modulation of cell-cell communication in the luteal phase. This study also represents the first comprehensive research of molecular mechanisms of BMP2 in the down-regulation Cx43 in luteinized human granulosa cells. Such data may provide valuable insights into ovarian physiology and benefit the development of potential therapeutic methods for patients suffering from luteal insufficiency. N/A. This research was supported by an operating grant from the China-Canadian Joint Health Research Initiative Grants Program to P.C.K. Leung and J.Z. Sheng. The authors declare no competing interest with the contents of this article.//////////////////
Bone morphogenetic protein 2 promotes primordial follicle formation in the ovary. Chakraborty P et al. (2015) Primordial follicles (PF) are formed when somatic cells differentiate into flattened pregranulosa cells, invaginate into the oocyte nests and encircle individual oocytes. We hypothesize that BMP2 regulates PF formation by promoting the transition of germ cells into oocytes and somatic cells into pregranulosa cells. E15 hamster ovaries were cultured for 8 days corresponding to postnatal day 8 (P8) in vivo, with or without BMP2, and the formation of PF was examined. BMP2 was expressed in the oocytes as well as ovarian somatic cells during development. BMP2 exposure for the first two days or the last two days or the entire 8 days of culture led to increase in PF formation suggesting that BMP2 affected both germ cell transition and somatic cell differentiation. Whereas an ALK2/3 inhibitor completely blocked BMP2-induced PF formation, an ALK2-specific inhibitor was partially effective, suggesting that BMP2 affected PF formation via both ALK2 and ALK3. BMP2 also reduced apoptosis in vitro. Further, more meiotic oocytes were present in BMP2 exposed ovaries. In summary, the results provide the first evidence that BMP2 regulates primordial follicle formation by promoting germ cell to oocyte transition and somatic cell to pre-granulosa cells formation and it acts via both ALK2 and ALK3.//////////////////
Souza CJ, et al 2002 reported the effect of bone morphogenetic protein 2 (BMP2) on oestradiol and
inhibin A production by sheep granulosa cells, and localization of
BMP receptors in the ovary by immunohistochemistry.
The bone morphogenetic proteins (BMPs) have been implicated in the paracrine
regulation of ovarian follicular development. The authors investigated the
expression of the BMP receptors (BMPRs) in sheep ovaries by immunohistochemistry
and the effect of BMP2, a natural ligand for these receptors, on granulosa cells
cultured in vitro. Ovaries from cyclic ewes were treated with polyclonal antibodies against BMPR1A, BMPR1B and
BMPR2. Strong immunostaining for all three receptors was observed in the granulosa
cell layer of follicles from the primary to late antral stages of development. Staining
was also present in the oocyte, corpus luteum, ovarian surface epithelium and, to a
lesser extent, the theca layer of antral follicles. For functional studies, granulosa cells
were obtained from immature follicles 1--3 mm in diameter. The cells were cultured
for 6 days in serum-free medium containing 1 ng oFSH-20 ml(minus sign1) in the
presence of 0, 3, 10 or 30 ng ml(minus sign1) human recombinant BMP2. The medium
was replaced every 2 days and oestradiol and inhibin A concentrations were
measured in the spent medium. In the absence of BMP2, oestradiol and inhibin A
production increased as the granulosa cells differentiated in vitro. The addition of the
highest dose of BMP2 enhanced oestradiol production (P < 0.05) without affecting the
proliferation of the cells. It is concluded that BMP receptors are present in sheep
ovaries and that BMPs may have a role in the differentiation of granulosa cells by
enhancing the action of FSH.
Expression regulated by
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Ovarian localization
Luteal cells
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Bone morphogenetic proteins are mediators of luteolysis in the human corpus luteum. Nio-Kobayashi J et al. (2015) Bone morphogenetic proteins (BMPs), members of the tumor growth factor β superfamily, play important roles in folliculogenesis in various species, however, little is known about their role in luteal function. In this study, we investigated the expression, regulation, and effects of BMP2, BMP4, and BMP6 in carefully-dated human corpora lutea and cultured human luteinized granulosa cells. The mRNA abundance of BMPs was increased in the regressing corpus luteum in vivo (P<0.01-0.001). Human chorionic gonadotropin (hCG) down-regulated BMP2, BMP4, and BMP6 transcripts both in vivo (P=0.05-0.001) and in vitro (P<0.001), and decreased the mRNA abundance of BMP receptors (BMPR1A, BMPR1B, BMPR2; P<0.05-0.01) in vitro. Three BMPs were regulated by differential signaling pathways. H89, a protein kinase A inhibitor, increased the expression of both BMP2 (P<0.05) and BMP4 (P<0.05) while decreasing BMP6 (P<0.01). PMA, a protein kinase C activator, decreased both BMP4 and BMP6 expression (P<0.0001) while enhancing the mRNA abundance of BMP2 (P<0.01). BMPs significantly down-regulated transcripts for LH/choriogonadotropin receptor (LHCGR; P<0.001) and steroidogenic acute regulatory protein (STAR; P<0.001), while up-regulating those of follicular stimulating hormone receptor (FSHR; P<0.01) and aromatase (CYP19A1; P<0.05-0.01) in vitro, possessing an effect opposite to hCG but similar to Activin A. Like Activin A, BMP4 and BMP6 stimulated the expression of Inhibin/Activin subunits with a marked effect on INHBB expression (P<0.05-0.01). These data confirm that BMPs are increased during luteal regression and negatively regulated by hCG via differential mechanisms, suggesting that BMPs are one of the mediators of luteolysis in women.//////////////////
DAN (NBL1) Specifically Antagonizes BMP2 and BMP4 and Modulates the Actions of GDF9, BMP2, and BMP4 in the Rat Ovary. Hung WT et al. Although differential screening-selected gene aberrative in neuroblastoma (DAN, official symbol NBL1) is the founding member of the DAN subfamily of bone morphogenetic protein (BMP) antagonists, its antagonizing targets, gene regulation and physiological functions remain unclear. Using diverse cell expression systems, we found that the generation of bioactive DAN is likely to be cell type-specific. Unlike other phylogenetically close members, which are covalently linked homodimers, DAN forms a noncovalently linked homodimer during folding. Purified recombinant DAN specifically blocked signaling of BMP2 and BMP4 but not that of other ovarian-expressed transforming growth factor- members. Although widely distributed in many organs, DAN transcript level was periodically regulated by gonadotropins. Ovarian microdissection indicated that NBL1 (DAN) mRNA is mainly expressed in granulosa cells, where its transcript level is up-regulated by the gonadotropin-driven cAMP cascade. We further investigated the local regulation and ovarian functions of DAN. NBL1 (DAN) mRNA expression in granulosa cells was up-regulated by oocyte-derived growth differentiation factor 9 (GDF9), whereas treatment with DAN significantly reversed the inhibitory effect of BMP4 on follicle-stimulating hormone-induced progesterone production in cultured granulosa cells. Our findings suggest the DAN gradient in granulosa cells, established by oocyte-derived GDF9, may serve as an antagonist barrier that modulates the actions of theca-derived BMP4 and granulosa/theca-derived BMP2 during folliculogenesis both spatially and temporally.