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In Vivo Delivery of Gremlin siRNA Plasmid Reveals Therapeutic Potential against Diabetic Nephropathy by Recovering Bone Morphogenetic Protein-7  [PDF]
Qingxian Zhang,Yonghong Shi,Jun Wada,Sandra M. Malakauskas,Maodong Liu,Yunzhuo Ren,Chunyang Du,Huijun Duan,Yingmin Li,Ying Li,Yanling Zhang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011709
Abstract: Diabetic nephropathy is a complex and poorly understood disease process, and our current treatment options are limited. It remains critical, then, to identify novel therapeutic targets. Recently, a developmental protein and one of the bone morphogenetic protein antagonists, Gremlin, has emerged as a novel modulator of diabetic nephropathy. The high expression and strong co-localization with transforming growth factor- β1 in diabetic kidneys suggests a role for Gremlin in the pathogenesis of diabetic nephropathy. We have constructed a gremlin siRNA plasmid and have examined the effect of Gremlin inhibition on the progression of diabetic nephropathy in a mouse model. CD-1 mice underwent uninephrectomy and STZ treatment prior to receiving weekly injections of the plasmid. Inhibition of Gremlin alleviated proteinuria and renal collagen IV accumulation 12 weeks after the STZ injection and inhibited renal cell proliferation and apoptosis. In vitro experiments, using mouse mesangial cells, revealed that the transfect ion of gremlin siRNA plasmid reversed high glucose induced abnormalities, such as increased cell proliferation and apoptosis and increased collagen IV production. The decreased matrix metalloprotease level was partially normalized by transfection with gremlin siRNA plasmid. Additionally, we observed recovery of bone morphogenetic protein-7 signaling activity, evidenced by increases in phosphorylated Smad 5 protein levels. We conclude that inhibition of Gremlin exerts beneficial effects on the diabetic kidney mainly through maintenance of BMP-7 activity and that Gremlin may serve as a novel therapeutic target in the management of diabetic nephropathy.
Gremlin-1 Induces BMP-Independent Tumor Cell Proliferation, Migration, and Invasion  [PDF]
Minsoo Kim, Soomin Yoon, Sukmook Lee, Seon Ah Ha, Hyun Kee Kim, Jin Woo Kim, Junho Chung
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0035100
Abstract: Gremlin-1, a bone morphogenetic protein (BMP) antagonist, is overexpressed in various cancerous tissues but its role in carcinogenesis has not been established. Here, we report that gremlin-1 binds various cancer cell lines and this interaction is inhibited by our newly developed gremlin-1 antibody, GRE1. Gremlin-1 binding to cancer cells was unaffected by the presence of BMP-2, BMP-4, and BMP-7. In addition, the binding was independent of vascular endothelial growth factor receptor-2 (VEGFR2) expression on the cell surface. Addition of gremlin-1 to A549 cells induced a fibroblast-like morphology and decreased E-cadherin expression. In a scratch wound healing assay, A549 cells incubated with gremlin-1 or transfected with gremlin-1 showed increased migration, which was inhibited in the presence of the GRE1 antibody. Gremlin-1 transfected A549 cells also exhibited increased invasiveness as well as an increased growth rate. These effects were also inhibited by the addition of the GRE1 antibody. In conclusion, this study demonstrates that gremlin-1 directly interacts with cancer cells in a BMP- and VEGFR2-independent manner and can induce cell migration, invasion, and proliferation.
Gremlin is Overexpressed in Lung Adenocarcinoma and Increases Cell Growth and Proliferation in Normal Lung Cells  [PDF]
Michael S. Mulvihill, Yong-Won Kwon, Sharon Lee, Li Tai Fang, Helen Choi, Roshni Ray, Hio Chung Kang, Jian-Hua Mao, David Jablons, Il-Jin Kim
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042264
Abstract: Background Gremlin, a member of the Dan family of BMP antagonists, is a glycosylated extracellular protein. Previously Gremlin has been shown to play a role in dorsal-ventral patterning, in tissue remodeling, and recently in angiogenesis. Evidence has previously been presented showing both over- and under-expression of Gremlin in different tumor tissues. Here, we sought to quantify expression of Gremlin in cancers of the lung and performed in vitro experiments to check whether Gremlin promotes cell growth and proliferation. Methodology/Principal Findings Expression of Gremlin in 161 matched tumor and normal lung cancer specimens is quantified by quantitative real-time PCR and protein level is measured by immunohistochemistry. GREM1 was transfected into lung fibroblast and epithelial cell lines to assess the impact of overexpression of Gremlin in vitro. Results Lung adenocarcinoma but not squamous cell carcinoma shows a significant increase in Gremlin expression by mRNA and protein level. Lung fibroblast and epithelial cell lines transfected with GREM1 show significantly increased cell proliferation. Conclusions/Significance Our data suggest that Gremlin acts in an oncogenic manner in lung adenocarcinoma and could hold promise as a new diagnostic marker or potential therapeutic target in lung AD or general thoracic malignancies.
Gremlin induces cell proliferation and extra cellular matrix accumulation in mouse mesangial cells exposed to high glucose via the ERK1/2 pathway
Huang Haixia,Huang Haiying,Li Ying,Liu Maodong
BMC Nephrology , 2013, DOI: 10.1186/1471-2369-14-33
Abstract: Background Gremlin, a bone morphogenetic protein antagonist, plays an important role in the pathogenesis of diabetic nephropathy (DN). However, the specific molecular mechanism underlying Gremlin’s involvement in DN has not been fully elucidated. In the present study, we investigated the role of Gremlin on cell proliferation and accumulation of extracellular matrix (ECM) in mouse mesangial cells (MMCs), and explored the relationship between Gremlin and the ERK1/2 pathway. Methods To determine expression of Gremlin in MMCs after high glucose (HG) exposure, Gremlin mRNA and protein expression were evaluated using real-time polymerase chain reaction and western blot analysis, respectively. To determine the role of Gremlin on cell proliferation and accumulation of ECM, western blot analysis was used to assess expression of pERK1/2, transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF). Cell proliferation was examined by bromodeoxyuridine (BrdU) ELISA, and accumulation of collagen IV was measured using a radioimmunoassay. This enabled the relationship between Gremlin and ERK1/2 pathway activation to be investigated. Results HG exposure induced expression of Gremlin, which peaked 12 h after HG exposure. HG exposure alone or transfection of normal-glucose (NG) exposed MMCs with Gremlin plasmid (NG + P) increased cell proliferation. Transfection with Gremlin plasmid into MMCs previously exposed to HG (HG + P) significantly increased this HG-induced phenomenon. HG and NG + P conditions up-regulated protein levels of TGF-β1, CTGF and collagen IV accumulation, while HG + P significantly increased levels of these further. Inhibition of Gremlin with Gremlin siRNA plasmid reversed the HG-induced phenomena. These data indicate that Gremlin can induce cell proliferation and accumulation of ECM in MMCs. HG also induced the activation of the ERK1/2 pathway, which peaked 24 h after HG exposure. HG and NG + P conditions induced overexpression of pERK1/2, whilst HG + P significantly induced levels further. Inhibition of Gremlin by Gremlin siRNA plasmid reversed the HG-induced phenomena. This indicates Gremlin can induce activation of the ERK1/2 pathway in MMCs. Conclusion Culture of MMCs in the presence of HG up-regulates expression of Gremlin. Gremlin induces cell proliferation and accumulation of ECM in MMCs. and enhances activation of the ERK1/2 pathway.
Tbx2 Terminates Shh/Fgf Signaling in the Developing Mouse Limb Bud by Direct Repression of Gremlin1  [PDF]
Henner F. Farin,Timo H-W. Lüdtke,Martina K. Schmidt,Susann Placzko,Karin Schuster-Gossler,Marianne Petry,Vincent M. Christoffels,Andreas Kispert
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003467
Abstract: Vertebrate limb outgrowth is driven by a positive feedback loop that involves Sonic hedgehog (Shh) and Gremlin1 (Grem1) in the posterior limb bud mesenchyme and Fibroblast growth factors (Fgfs) in the overlying epithelium. Proper spatio-temporal control of these signaling activities is required to avoid limb malformations such as polydactyly. Here we show that, in Tbx2-deficient hindlimbs, Shh/Fgf4 signaling is prolonged, resulting in increased limb bud size and duplication of digit 4. In turn, limb-specific Tbx2 overexpression leads to premature termination of this signaling loop with smaller limbs and reduced digit number as phenotypic manifestation. We show that Tbx2 directly represses Grem1 in distal regions of the posterior limb mesenchyme allowing Bone morphogenetic protein (Bmp) signaling to abrogate Fgf4/9/17 expression in the overlying epithelium. Since Tbx2 itself is a target of Bmp signaling, our data identify a growth-inhibiting positive feedback loop (Bmp/Tbx2/Grem1). We propose that proliferative expansion of Tbx2-expressing cells mediates self-termination of limb bud outgrowth due to their refractoriness to Grem1 induction.
Morphogenetic Protein rhBMP-2 and New Bone Formation
Issa,Jo?o Paulo Mardegan; Nascimento,Cássio do; Barbosa,Rodrigo Edson dos Santos; Mello,Amaro Sérgio da Silva; Iyomasa,Mamie Mizusaki;
International Journal of Morphology , 2006, DOI: 10.4067/S0717-95022006000400005
Abstract: this work aim to show by literature review the principal characteristics of morphogenetic proteins, in special of the rhbmp-2, with the major osteoinductive properties, presented in the prime works count from it discovery until actually, showing the most varieties and applications of this protein
Role of RGM coreceptors in bone morphogenetic protein signaling
Peter J Halbrooks, Ru Ding, John M Wozney, Gerard Bain
Journal of Molecular Signaling , 2007, DOI: 10.1186/1750-2187-2-4
Abstract: Here, we investigate whether RGMa, RGMb, and RGMc play required roles in BMP and TGFβ signaling in the mouse myoblast C2C12 cell line. These cells are responsive to BMPs and are frequently used to study BMP/TGFβ signaling pathways. Using siRNA reagents to specifically knock down each RGM protein, we show that the RGM co-receptors are required for significant BMP signaling as reported by two cell-based BMP activity assays: endogenous alkaline phosphatase activity and a luciferase-based BMP reporter assay. Similar cell-based assays using a TGFβ-induced luciferase reporter show that the RGM co-receptors are not required for TGFβ signaling. The binding interaction of each RGM co-receptor to each of BMP2 and BMP12 is observed and quantified, and equilibrium dissociation constants in the low nanomolar range are reported.Our results demonstrate that the RGMs play a significant role in BMP signaling and reveal that these molecules cannot functionally compensate for one another.The transforming growth factor β (TGFβ) superfamily of ligands, which includes the TGFβ proteins, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), and others, plays a key role in regulating cell proliferation, differentiation, migration, and apoptosis in a diverse set of developmental and physiological pathways. These secreted signaling proteins exert crucial functions at several stages of development and are essential for tissue repair and maintenance in the adult [1-4]. The pathogenesis in a host of diseases, including cancer, osteoporosis, and fibrosis, has been attributed to disregulated TGFβ superfamily function [5]. The BMPs, the largest subgroup within the TGFβ superfamily, participate in the development of nearly all organs and play a critical role in the formation and repair of bone [6,7]. The TGFβ s are known to play important roles in cellular proliferation and differentiation, inflammation and tissue repair, and host immunity [4,8,9].TGFβ family ligands mediat
The orosomucoid 1 protein (α1 acid glycoprotein) is overexpressed in odontogenic myxoma
García-Mu?oz Alejandro,Rodríguez Mario A,Bologna-Molina Ronell,Cázares-Raga Febe E
Proteome Science , 2012, DOI: 10.1186/1477-5956-10-49
Abstract: Background Odontogenic myxoma (OM) is a benign, but locally invasive, neoplasm occurring in the jaws. However, the molecules implicated in its development are unknown. OM as well as Dental Follicle (DF), an odontogenic tissue surrounding the enamel organ, is derived from ectomesenchymal/mesencyhmal elements. To identify some protein that could participate in the development of this neoplasm, total proteins from OM were separated by two-dimensional electrophoresis and the profiles were compared with those obtained from DF, used as a control. Results We identified eight proteins with differential expression; two of them were downregulated and six upregulated in OM. A spot consistently overexpressed in odontogenic myxoma, with a molecular weight of 44-kDa and a pI of 3.5 was identified as the orosomucoid 1 protein. Western blot experiments confirmed the overexpression of this protein in odontogenic myxoma and immunohistochemical assays showed that this protein was mainly located in the cytoplasm of stellate and spindle-shaped cells of this neoplasm. Conclusion Orosomucoid 1, which belongs to a group of acute-phase proteins, may play a role in the modulation of the immune system and possibly it influences the development of OM.
Suppression of bone morphogenetic protein inhibitors promotes osteogenic differentiation: therapeutic implications
Manolis Heliotis, Eleftherios Tsiridis
Arthritis Research & Therapy , 2008, DOI: 10.1186/ar2467
Abstract: Bone morphogenetic proteins (BMPs), a distinct transforming growth factor (TGF)-β subgroup that is also involved in organogenesis, have been shown to be expressed during various stages of bone healing process. Mesenchymal stem cells (MSCs) that are capable of differentiation toward the osteogenic lineage are recruited from local deposits or the circulation to initiate callous formation. Kwong and coworkers [1], in their recent report, presented the expression of BMP-2 and its inhibitor chordin in human MSCs undergoing differentiation in an osteogenic medium. Temporal and spatial expression of BMPs, has attracted research interest because a number of its members, namely BMP-2, -7, -9 and -14, can induce de novo bone formation [2].BMPs bind to two different type I and type II serine/threonine kinase receptors. BMP heteromeric receptor complexes activate intracellular proteins known as Smads (small 'mothers against' decapentaplegic), including regulating R-Smads (Smad1, Smad5 and Smad8), common co-Smad (Smad4), and inhibitory I-Smads (Smad6 and Smad7), which translocate to the nucleus activating specific target genes [3].BMP inhibitors regulate local negative feedback mechanisms. Some act extracellularly, preventing BMP binding to receptors, whereas others act intracellularly, inhibiting Smad downstream activation.The most studied BMP inhibitor, noggin, reduces the activity of both osteoblasts and osteoclasts, leading to osteopenia and nonhealing fractures. In contrast, noggin knockout leads to irregularly thickened long bones and is lethal shortly after birth [4]. Chordin has a similar action to noggin. It antagonizes BMP-2, -4 and -7 by preventing them from activating BMP receptors, augmented by the co-factor twisted gastrulation (Tsg) [5]. This causes a decrease in osteogenic differentiation and a reduction in BMP-2 and BMP-4 expression [1,5]. Gremlin, another extracellular inhibitor of BMP-2, -4 and -7 engineered in transgenic mice, suppresses osteoblasts with cons
Promotion of Bone Morphogenetic Protein Signaling by Tetraspanins and Glycosphingolipids  [PDF]
Zhiyu Liu?,Herong Shi?,Lindsey C. Szymczak?,Taner Aydin?,Sijung Yun?,Katharine Constas?,Arielle Schaeffer?,Sinthu Ranjan?,Saad Kubba?,Emad Alam
PLOS Genetics , 2015, DOI: 10.1371/journal.pgen.1005221
Abstract: Bone morphogenetic proteins (BMPs) belong to the transforming growth factor β (TGFβ) superfamily of secreted molecules. BMPs play essential roles in multiple developmental and homeostatic processes in metazoans. Malfunction of the BMP pathway can cause a variety of diseases in humans, including cancer, skeletal disorders and cardiovascular diseases. Identification of factors that ensure proper spatiotemporal control of BMP signaling is critical for understanding how this pathway is regulated. We have used a unique and sensitive genetic screen to identify the plasma membrane-localized tetraspanin TSP-21 as a key new factor in the C. elegans BMP-like “Sma/Mab” signaling pathway that controls body size and postembryonic M lineage development. We showed that TSP-21 acts in the signal-receiving cells and genetically functions at the ligand-receptor level. We further showed that TSP-21 can associate with itself and with two additional tetraspanins, TSP-12 and TSP-14, which also promote Sma/Mab signaling. TSP-12 and TSP-14 can also associate with SMA-6, the type I receptor of the Sma/Mab pathway. Finally, we found that glycosphingolipids, major components of the tetraspanin-enriched microdomains, are required for Sma/Mab signaling. Our findings suggest that the tetraspanin-enriched membrane microdomains are important for proper BMP signaling. As tetraspanins have emerged as diagnostic and prognostic markers for tumor progression, and TSP-21, TSP-12 and TSP-14 are all conserved in humans, we speculate that abnormal BMP signaling due to altered expression or function of certain tetraspanins may be a contributing factor to cancer development.
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