Humans ; Pulmonary Arterial Hypertension ; Bone Morphogenetic Protein Receptors, Type II/metabolism* ; Pedigree ; Mutation ; Familial Primary Pulmonary Hypertension

The occurrence and development of pulmonary arterial hypertension (PAH) is closely related to the genetic mutation of bone morphogenetic protein receptor type II (BMPRII) encoding gene and the inflammatory response mediated by nuclear factor κB (NF-κB) pathway. This paper was aimed to investigate the effect of NF-κB pathway inhibitors on lipopolysaccharide (LPS)-induced pulmonary artery endothelial cell injury. Human pulmonary artery endothelial cells were treated with 1 μg/mL of LPS. The expression levels of BMPRII and interleukin-8 (IL-8) were detected by Western blot and qPCR. The rat PAH model was established by intraperitoneal (i.p.) injection of monocrotaline (MCT). The expression levels of BMPRII and IL-8 in pulmonary artery endothelial cells were detected by immunofluorescence staining. Cardiac hemodynamic changes and pulmonary vascular remodeling were detected in the MCT-PAH model rats. The results showed that LPS caused down-regulation of BMPRII expression and up-regulation of IL-8 expression in human pulmonary artery endothelial cells. NF-κB inhibitor BAY11-7082 (10 μmol/L) reversed the effect of LPS. In the pulmonary artery endothelial cells of MCT-PAH model, BMPRII expression was down-regulated, IL-8 expression was up-regulated, weight ratio of right ventricle to left ventricle plus septum [RV/(LV+S)] and right ventricular systolic pressure (RVSP) were significantly increased, cardiac output (CO) and tricuspid annular plane systolic excursion (TAPSE) were significantly reduced, and pulmonary vessel wall was significantly thickened. BAY11-7082 (5 mg/kg, i.p., 21 consecutive days) reversed the above changes in the MCT-PAH model rats. These results suggest that LPS down-regulates the expression level of BMPRII through NF-κB signaling pathway, promoting the occurrence and development of PAH. Therefore, the NF-κB pathway can be used as a potential therapeutic target for PAH.
Animals ; Bone Morphogenetic Protein Receptors, Type II ; Down-Regulation ; Endothelial Cells/metabolism* ; Humans ; Hypertension, Pulmonary/drug therapy* ; Lipopolysaccharides ; NF-kappa B/metabolism* ; Rats ; Rats, Sprague-Dawley ; Vascular Remodeling

Bone morphogenetic proteins (BMPs) are the largest subfamily of the transforming growth factor-β superfamily, and they play important roles in the development of numerous organs, including the inner ear. The inner ear is a relatively small organ but has a highly complex structure and is involved in both hearing and balance. Here, we discuss BMPs and BMP signaling pathways and then focus on the role of BMP signal pathway regulation in the development of the inner ear and the implications this has for the treatment of human hearing loss and balance dysfunction.
Body Patterning ; Bone Morphogenetic Protein Receptors/physiology* ; Bone Morphogenetic Proteins/physiology* ; Cell Differentiation ; Cochlea/embryology* ; Ear, Inner/embryology* ; Hedgehog Proteins/physiology* ; Humans ; Signal Transduction/physiology* ; Smad Proteins/physiology* ; Vestibule, Labyrinth/embryology* ; Wnt Signaling Pathway

Objective: To induce hypospadias in male rat offspring by maternal exposure to di-n-butyl phthalate (DBP) during late pregnancy and further investigate its mechanisms. METHODS: We randomly divided 20 pregnant rats into a DBP exposure and a control group, the former treated intragastrically with DBP while the latter with soybean oil at 750 mg per kilogram of the body weight per day from gestation days (GD) 14 to 18. On postnatal day (PND) 1, we recorded the incidence rate of hypospadias and observed the histopathological changes in the genital tubercle of the hypospadiac rats. We also measured the level of serum testosterone (T) by radioimmunoassay and determined the mRNA and protein expressions of the androgen receptor (AR), sonic hedgehog (Shh), bone morphogenetic protein 4 (Bmp4) and fibroblast growth factor 8 (Fgf8) in the genital tubercle by real-time PCR and Western blot. RESULTS: No hypospadiac male rats were found in the control group. The incidence rate of hypospadias in male offspring was 43.6% in the DBP-treatment group. Histological analysis confirmed hypospadiac malformation. The serum testosterone concentration was decreased in the hypospadiac male rats as compared with the controls (［0.49 ± 0.05］ vs ［1.12 ± 0.05］ ng/ml, P <0.05). The mRNA expressions of AR, Shh, Bmp4 and Fgf8 in the genital tubercle were significantly lower in the hypospadiac male rats than in the controls (AR: 0.50 ± 0.05 vs 1.00 ± 0.12, P <0.05; Shh: 0.65 ± 0.07 vs 1.00 ± 0.15, P <0.05; Bmp4: 0.42 ± 0.05 vs 1.00 ± 0.13, P <0.05; Fgf8: 0.46 ± 0.04 vs 1.00 ± 0.12, P <0.05), and so were their protein expressions (AR: 0.34 ± 0.05 vs 1.00 ± 0.09, P <0.05; Shh: 0.51 ± 0.07 vs 1.00 ± 0.12, P <0.05; Bmp4: 0.43 ± 0.05 vs 1.00 ± 0.11, P <0.05; Fgf8: 0.57 ± 0.04 vs 1.00 ± 0.13, P <0.05). CONCLUSIONS Maternal exposure to DBP during late pregnancy can induce hypospadias in the male rat offspring. DBP affects the development of the genital tubercle by reducing the serum T concentration and expressions of AR, Shh, Bmp4 and Fgf8 in the genital tubercle, which might underlie the mechanism of DBP inducing hypospadias.
Animals ; Body Weight ; Bone Morphogenetic Protein 4 ; blood ; Dibutyl Phthalate ; toxicity ; Female ; Fibroblast Growth Factor 8 ; blood ; Hedgehog Proteins ; blood ; Hypospadias ; blood ; chemically induced ; pathology ; Male ; Maternal Exposure ; Plasticizers ; toxicity ; Pregnancy ; RNA, Messenger ; blood ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, Androgen ; blood ; Soybean Oil ; Testosterone ; blood

Human telomerase reverse transcriptase (hTERT) plays a central role in telomere lengthening for continuous cell proliferation, but it remains unclear how extracellular cues regulate telomerase lengthening of telomeres. Here we report that the cytokine bone morphogenetic protein-7 (BMP7) induces the hTERT gene repression in a BMPRII receptor- and Smad3-dependent manner in human breast cancer cells. Chonic exposure of human breast cancer cells to BMP7 results in short telomeres, cell senescence and apoptosis. Mutation of the BMPRII receptor, but not TGFbRII, ACTRIIA or ACTRIIB receptor, inhibits BMP7-induced repression of the hTERT gene promoter activity, leading to increased telomerase activity, lengthened telomeres and continued cell proliferation. Expression of hTERT prevents BMP7-induced breast cancer cell senescence and apoptosis. Thus, our data suggest that BMP7 induces breast cancer cell aging by a mechanism involving BMPRII receptor- and Smad3-mediated repression of the hTERT gene.
Actin-Related Protein 2 ; genetics ; metabolism ; Activin Receptors, Type II ; genetics ; metabolism ; Bone Morphogenetic Protein 7 ; genetics ; metabolism ; Bone Morphogenetic Protein Receptors, Type II ; genetics ; metabolism ; Breast Neoplasms ; genetics ; metabolism ; Cellular Senescence ; Female ; HeLa Cells ; Humans ; MCF-7 Cells ; Neoplasm Proteins ; genetics ; metabolism ; Protein-Serine-Threonine Kinases ; genetics ; metabolism ; Receptor, Transforming Growth Factor-beta Type II ; Receptors, Transforming Growth Factor beta ; genetics ; metabolism ; Smad3 Protein ; genetics ; metabolism ; Telomerase ; genetics ; metabolism ; Telomere Homeostasis

INTRODUCTIONThe aim of this study was to determine the effect of a high-fat diet (HFD) on oocyte maturation and quality in a mouse model.

METHODSFemale BALB/c mice were allocated to one of the following groups: (a) control group (n = 40), which received a controlled diet; or (b) HFD group (n = 40), which received an HFD for 12 weeks. Sections of the ovary were examined histologically. The number of follicles and corpora lutea were counted. In vitro maturation and in vitro fertilisation (IVF) were assessed in germinal vesicle (GV) and metaphase II (MII) oocytes, respectively. The expression of bone morphogenetic protein 15 (BMP15) and leptin receptor genes in GV and MII oocytes was evaluated using reverse transcription real-time polymerase chain reactions.

RESULTSIn the HFD group, there was a decreased number of primordial and Graafian follicles, as well as corpora lutea (p < 0.05). The rate of oocyte development to the MII stage was also reduced (p < 0.001). Cumulus expansion was observed more frequently in the control group than the HFD group (p < 0.05). The IVF rate in the HFD group was lower than that in the control group (p < 0.05). In the HFD group, BMP15 and leptin receptor genes were upregulated in the GV stage (p > 0.05) and MII stage (p < 0.05), compared to the control group.

CONCLUSIONAn HFD reduces folliculogenesis in the primordial and Graafian stages, in vitro maturation and in vitro fertilisation rates, as well as oocyte quality in mice.

Animals ; Body Weight ; Bone Morphogenetic Protein 15 ; metabolism ; Corpus Luteum ; pathology ; Diet, High-Fat ; Female ; Fertility ; Fertilization in Vitro ; methods ; Gene Expression Regulation ; Metaphase ; Mice ; Mice, Inbred BALB C ; Obesity ; complications ; Oocytes ; cytology ; pathology ; Ovarian Follicle ; pathology ; Ovary ; metabolism ; pathology ; Photography ; Polymerase Chain Reaction ; Receptors, Leptin ; metabolism

Bone Morphogenetic Protein Receptors, Type II ; metabolism ; Endothelium ; drug effects ; metabolism ; Hypertension, Pulmonary ; drug therapy ; metabolism ; pathology ; Signal Transduction ; drug effects

OBJECTIVETo observe the expression pattern of bone morphogenetic protein receptor IA (BMPR IA) in rats after contusive spinal cord injury.

METHODSThe expressions of BMPR IA, IB, and II were detected by immunochemistry in the spinal cord of normal adult rats, and the expression of BMPR IA was detected in the infinite horizons impactor model at 1, 3, 7, 14, 30, and 60 days after spinal cord injury.

RESULTSIn the spinal cord of normal adult rats, BMPR IA and II were expressed predominantly in the oligodentrocytes and neurons in the grey matter, and also in some astrocytes and numerous microglia cells. Only a low level of BMPR IB expression was detected in the neurons of the grey matter. After spinal cord injury, the expression of BMP IA markedly increased with sustained strong expression in the astrocytes till one month after the injury; its expression was also increased obviously in the microglia cells activated by the injury.

CONCLUSIONThe expression of BMPR IA increases significantly in the astrocytes and activated microglia cells in rats after contusive spinal cord injury, suggesting the involvement of BMP signaling pathway in the physiological and pathological role of glia cells.

Animals ; Astrocytes ; metabolism ; Bone Morphogenetic Protein Receptors, Type I ; metabolism ; Female ; Microglia ; metabolism ; Rats ; Rats, Sprague-Dawley ; Spinal Cord Injuries ; metabolism

OBJECTIVETo study the role of antenatal glucocorticoid (dexamethasone and betamethasone) on bone morphogenetic protein (BMP) signal transduction of the rat fetal lungs.

METHODSFifteen pregnant rats were randomly divided into five groups: the rats treated with dexamethasone for 1 day (1D-DEX) or 3 days (3D-DEX), with betamethasone for 1 day (1D-BEX) or 3 days (3D-BEX) or with normal saline (control group), followed cesarean section on the 19th day of gestation. The mRNA levels of BMP4, BMPR-II, Smad1 and ATF-2 of fetal rat lungs were ascertained by reverse transcriptase polymerase chain reaction (RT-PCR). The expression of BMP4, BMPR-II, Smad1 and ATF-2 antigen expression in fetal lungs was assessed by immune histochemical staining. The expression of BMP4 and BMPR-II was determined by Western blot.

RESULTSThe levels of BMP4, BMPR-II and Smad1 mRNA expression were up-regulated in the 1D-BEX, 3D-BEX and 3D-DEX groups compared with those in the control group (P<0.05). The immune histochemiscal analysis showed that the expression of BMP4, BMPR-II, Phospho-Smad1 (pSmad1) and ATF-2 in the 1D-BEX, 3D-BEX and 3D-DEX groups was significantly higher than that in the control group (P<0.01). The results of Western blot demonstrated that the expression of BMP4 and BMPR-II protein increased significantly in the 1D-BEX, 3D-BEX and 3D-DEX groups when compared with the control group (P<0.01).

CONCLUSIONSBetamethasone and dexamethasone may play important roles in the regulation of BMP signal transduction in the rat fetal lungs. Up-regulation of BMP4, BMPR-II and Smad1 might be one of crucial factors for the glucocorticoid-induced maturity of fetal lungs.

Activating Transcription Factor 2 ; analysis ; genetics ; Animals ; Betamethasone ; pharmacology ; Bone Morphogenetic Protein 4 ; analysis ; genetics ; physiology ; Bone Morphogenetic Protein Receptors, Type II ; analysis ; genetics ; Dexamethasone ; pharmacology ; Female ; Fetus ; drug effects ; metabolism ; Lung ; drug effects ; metabolism ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; drug effects ; Smad1 Protein ; analysis ; genetics

PURPOSE: Several signaling pathways have been shown to regulate the lineage commitment and terminal differentiation of bone marrow stromal cells (BMSCs). Bone morphogenetic protein (BMP) signaling has important effects on the process of skeletogenesis. In the present study, we tested the role of bone morphogenetic protein receptor (BMPR) in the osteogenic differentiation of rat bone marrow stromal cells in osteogenic medium (OM) with or without BMP-2. MATERIALS AND METHODS: BMSCs were harvested from rats and cultured in OM containing dexamethasone, beta-glycerophosphate, and ascorbic acid, with or without BMP-2 in order to induce osteogenic differentiation. The alkaline phosphatase (ALP) activity assay and von kossa staining were used to assess the osteogenic differentiation of the BMSCs. BMPR mRNA expression was assessed using reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The BMSCs that underwent osteogenic differentiation in OM showed a higher level of ALP activity and matrix mineralization. BMP-2 alone induced a low level of ALP activity and matrix mineralization in BMSCs, but enhanced the osteogenic differentiation of BMSCs when combined with OM. The OM significantly induced the expression of type IA receptor of BMPR (BMPRIA) and type II receptor of BMPR (BMPRII) in BMSCs after three days of stimulation, while BMP-2 significantly induced BMPRIA and BMPRII in BMSCs after nine or six days of stimulation, respectively. CONCLUSION: BMSCs commit to osteoblastic differentiation in OM, which is enhanced by BMP-2. In addition, BMP signaling through BMPRIA and BMPRII regulates the osteogenic differentiation of rat BMSCs in OM with or without BMP-2.
Alkaline Phosphatase/metabolism ; Animals ; Bone Marrow Cells/*cytology/drug effects/*metabolism ; Bone Morphogenetic Protein 2/pharmacology ; Bone Morphogenetic Protein Receptors/genetics/*metabolism ; *Cell Differentiation/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Culture Media/pharmacology ; Male ; Osteogenesis/drug effects/genetics ; Rats ; Rats, Wistar ; Reverse Transcriptase Polymerase Chain Reaction ; Stromal Cells/*cytology/drug effects/*metabolism