Transforming growth factor beta1 (TGFbeta1) is a potent growth inhibitor for most cells, including neoplastic cells. However, there are several types of malignant cells that are resistant to its growth-inhibitory effect. LMC19, a highly malignant rat urothelial cell line, lacks TGFbeta1 receptor (TbetaRI) and is insensitive to the growth-suppresive effect of TGFbeta1. We transfected an expression vector containing human TbetaRI into this cell line. In control cells transfected with the neo gene alone, no inhibitory effect on growth was observed in vitro by the addition of anti-TGFbeta1 antibody or recombinant TGFbeta1 into serum-free medium. In contrast, the growth of all transfectants tested was inhibited significantly under serum-free conditions because of their endogenous TGFbeta synthesis. The growth was reduced further by the addition of recombinant TGFbeta1. This response pattern is consistent with TGFbeta1 mediating its effects by an autocrine and paracrine mechanism. The tumorigenicity ...
Plasmid pRK5 TGF beta type I receptor (T202D) Flag from Dr. Rik Deryncks lab contains the insert TGF beta type I receptor and is published in J Biol Chem. 1996 May 31. 271(22):13123-9. This plasmid is available through Addgene.
1PY5: Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain.
The TGF-β superfamily is a large family of growth and differentiation factors that regulate a wide variety of cellular processes in many different cell types and biological contexts. Different family members regulate cell proliferation (both positively and negatively), migration, extracellular matrix elaboration, adhesion, survival and differentiation, in both developing embryos and adult organisms, ranging from worms to humans (Whitman, 1998; Massagué and Chen, 2000; Massagué et al., 2000). Aberrant signaling by TGF-β, the prototype of the family, has been implicated in a number of human diseases, including cancer, hereditary hemorrhagic telangiectasia, atherosclerosis, and fibrotic disease of the kidney, liver, and lung (Blobe et al., 2000). In addition, low levels of TGF-β signaling have been implicated in compromised wound healing, and inappropriately high levels of TGF-β signaling are associated with excessive scarring (Roberts and Sporn, 1993).. The mechanism of signaling by TGF-β ...
TGF-β 3 superfamily is a group of multifunctional cytokines that affect cell growth, differentiation, apoptosis, and morphogenesis (1, 2, 3) . This family consists of ,40 family members, including TGF-βs, activins, and BMPs. TGF-β superfamily ligands induce heteromeric complex formation of cognate type II and type I serine/threonine kinase receptors. Type II receptor kinases then phosphorylate serine and threonine residues in the GS domain of type I receptors, which results in the activation of type I receptor kinases (4) . Activated type I receptors signal into cytoplasm through phosphorylation of Smad proteins. Thus far, eight mammalian Smad proteins have been identified. Smad1, Smad2, Smad3, Smad5, and Smad8 are R-Smads, which are directly phosphorylated by type I receptors. Smad2 and Smad3 are activated by the TGF-β type I receptor and the activin type IB receptor, whereas Smad1, Smad5, and Smad8 are activated by BMP type I receptors and activin receptor-like kinase 1. Smad4 is a Co-Smad ...
This gene encodes a type I cell-surface receptor for the TGF-beta superfamily of ligands. It shares with other type I receptors a high degree of similarity in serine-threonine kinase subdomains, a glycine- and serine-rich region (called the GS domain) preceding the kinase domain, and a short C-terminal tail. The encoded protein, sometimes termed ALK1, shares similar domain structures with other closely related ALK or activin receptor-like kinase proteins that form a subfamily of receptor serine/threonine kinases. Mutations in this gene are associated with hemorrhagic telangiectasia type 2, also known as Rendu-Osler-Weber syndrome 2. [provided by RefSeq, Jul 2008 ...
Using a mix of wild-type (WT) and caveolin-2 (Cav-2) knockout along with retroviral reexpression approaches, we offer the data for the negative role of Cav-2 in regulating anti-proliferative function and signaling of changing growth matter (TGF-) in endothelial cells (ECs). evidenced by three unbiased proliferation assays: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), cell count number, and bromodeoxyuridine incorporation and correlated with a lack of TGF-mediated upregulation of cell routine inhibitor Rabbit polyclonal to PAI-3 p27 and following Rebastinib reduced amount of the degrees of hyperphosphorylated (inactive) type of the retinoblastoma protein in Cav-2 reexpressing ECs. Mechanistically, Cav-2 inhibits anti-proliferative action of TGF- by suppressing Alk5-Smad2/3 pathway manifested by reduced magnitude and amount of TGF-induced Smad2/3 phosphorylation aswell as activation of activin receptor-like kinase-5 (Alk5)-Smad2/3 target genes plasminogen activator ...
J:28212 Iseki S, Osumi-Yamashita N, Miyazono K, Franzen P, Ichijo H, Ohtani H, Hayashi Y, Eto K, Localization of transforming growth factor-beta type I and type II receptors in mouse development. Exp Cell Res. 1995 Aug;219(2):339-47 ...
Following myocardial infarction (MI), the heart undergoes a pathological process known as remodeling, which in many instances results in cardiac dysfunction and ultimately heart failure and death. Transforming growth factor-beta (TGF-beta) is a key m
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A fresh water-soluble polysaccharide (longan polysaccharide 1 (LP1)) was extracted and successfully purified from pulp via diethylaminoethyl (DEAE)-cellulose anion-exchange and Sephacryl S-300 HR gel chromatography. HO8910 tumor cells, with inhibition percentages of Tasquinimod supplier 40% and 50%, respectively. In addition, LP1 significantly stimulated the production of the cytokine interferon- (IFN-), increased the activity of murine […]. ...
Mohammad KS, Chen CG, Balooch G, Stebbins E, McKenna CR, Davis H, Niewolna M, Peng XH, Nguyen DH, Ionova-Martin SS, Bracey JW, Hogue WR, Wong DH, Ritchie RO, Suva LJ, Derynck R, Guise TA, Alliston T. Pharmacologic inhibition of the TGF-beta type I receptor kinase has anabolic and anti-catabolic effects on bone. PLoS One. 2009; 4(4):e5275 ...
Purpose: Activin receptor-like kinase 1 (ALK1) is a novel target in angiogenesis. Concurrent targeting of ALK1 and VEGF signaling results in augmented inhibition of tumor growth in renal cell carcinoma (RCC) xenograft models. Dalantercept is an ALK1-receptor fusion protein that acts as a ligand trap for bone morphogenetic proteins 9 and 10. The DART Study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept plus axitinib in patients with advanced RCC and determined the optimal dose for further testing.. Experimental Design: Patients received dalantercept 0.6, 0.9, or 1.2 mg/kg subcutaneously every 3 weeks plus axitinib 5 mg by mouth twice daily until disease progression or intolerance.. Results: Twenty-nine patients were enrolled in the dose escalation (n = 15) and expansion (n = 14) cohorts. There were no dose-limiting toxicities or grade 4/5 treatment-related adverse events. In addition to common VEGFR tyrosine kinase inhibitor effects, ...
This multicenter study evaluated the clinical activity and toxicity of ganetespib in molecularly defined cohorts of patients with advanced NSCLCs. Durable objective responses and disease stabilization occurred in the majority of patients with disease harboring ALK gene rearrangement who were crizotinib-naïve. In NSCLCs, ALK rearrangement results in the expression of one of several variants of the EML4-ALK fusion protein, which results in a constitutively active ALK kinase capable of activating downstream signaling cascades that promote cell proliferation and survival (5, 35, 36). In preclinical studies, ALK inhibition has been shown to induce cell death and tumor regression (17, 36, 37). The data from this trial and the recent study of IPI-504 suggest that in addition to direct tyrosine kinase inhibition, ALK can be disabled by Hsp90 inhibition, confirming preclinical predictions (17, 18). The Hsp90-inhibitory activity of ganetespib is further validation for the clinical value of this class of ...
Olsen, Oddrun Elise; Wader, Karin Fahl; Misund, Kristine; Våtsveen, Thea Kristin; Rø, Torstein Baade; Størdal, Berit Fladvad; Moen, Siv Helen; Standal, Therese; Waage, Anders; Sundan, Anders; Holien, Toril. (2013) Bone morphogenetic protein-9 suppresses growth of myeloma cells by signaling through ALK2 but is inhibited by endoglin. TGF-B Superfamily: Signaling in Development and Disease . FASEB; 2013-07-28 - 2013-08-02. ...
8.0 8.1 Bauer, H et al. (2001) The type I serine/threonine kinase receptor Alk8/Lost-a-fin is required for Bmp2b/7 signal transduction during dorsoventral patterning of the zebrafish embryo. Development 128 849-58 PubMed GONUTS page ...
Actriţa de origine portoricană Miriam Colon, cunoscută pentru rolul mamei lui Al Pacino din Scarface (1983), a murit la vârsta de 80 de ani, anunţă Variety.
Fibrodysplasia ossificans progressiva (FOP; MIM 135100) is a rare autosomal dominant disease characterized by progressive heterotopic ossification of soft connective tissues including skeletal muscle, tendons and ligaments. Individuals with FOP appear normal at birth, except for malformed great toes and thumbs. The ossification begins in early childhood and progresses over the course of a lifetime. It leads to a debilitating ankylosis of all major joints of the axial and appendicular skeleton and most patients will be confined to wheelchair by the third decade of life. Most FOP cases are sporadic, but there are reports of affected siblings. FOP is caused by mutations in the ACVR1 gene that codes for activin A receptor, type I. It belongs to the protein kinase superfamily and functions as a receptor for bone morphogenetic proteins (BMPs). BMPs are extracellular signaling proteins that are critical for the early development of heart, central nervous system, cartilage, and bone. All of the ACVR1 ...
Fibrodysplasia ossificans progressiva (FOP) is a rare and disabling genetic condition characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomic patterns. {file27251}{file27252}Most cases arise as a result of a spontaneous new mutation.
MONTREAL, CANADA, June 13, 2016 - Clementia is pleased to announce that the Phase 2 Open-label Extension Trial (PVO-1A-202) has been modified to enroll up to 20 new participants and to investigate new palovarotene dosing regimens in participants with fibrodysplasia ossificans progressiva (FOP). The modification to the Phase 2 Open-label extension trial is designated as Part B.. The Phase 2 Trial (Study PVO-1A-201), which is now complete, was designed as an exploratory dose-ranging study that examined the safety and efficacy of two different dosing regimens of palovarotene in participants for acute flare-up. All 40 individuals who completed the Phase 2 trial have enrolled into the Phase 2 Open-label Extension Trial, which provides access to palovarotene to any participant experiencing an eligible flare-up and continues to evaluate the long-term safety and efficacy of palovarotene.. Much has been learned from these studies. Emerging data suggests that the risk to develop heterotopic ossification ...
... (FOP), also known as Stone Man Syndrome, is a very rare inherited disorder in which muscle tissue and connective tis
Looking for online definition of TGF-beta type I receptor in the Medical Dictionary? TGF-beta type I receptor explanation free. What is TGF-beta type I receptor? Meaning of TGF-beta type I receptor medical term. What does TGF-beta type I receptor mean?
We further explored the physiologic significance of the ability of ACVR1[R206H] to respond to activin A in our mouse model of FOP. Inhibition of activin A with a blocking antibody completely inhibited development of HO. Although our results do not exclude the possibility that other ligands may participate, they indicate that activin A (and perhaps the activin A-containing heterodimers, activin AB and AC) must play a major, indeed obligate, role. Moreover, our data were consistent with the idea that activin A, normally produced by cells of the immune system during inflammation (22, 23), is co-opted and reinterpreted by ACVR1[R206H]-expressing cells with osteogenic potential. Hence, activin A may provide the missing link between inflammation and HO in FOP.. We would like to caution, however, that there is a paucity of data implicating activin A as the driver of HO in FOP patients per se; this is largely due to the inability to safely biopsy patients in between, or during, attacks. We cannot ...
Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high-throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of ...
Results All patients presented small asymptomatic lesions similar to hamartomas at the level of the dorsal medulla and ventral pons, associated with minor brainstem dysmorphisms and abnormal origin of the vestibulocochlear and facial nerves. The size of the brainstem lesions did not correlate with patients age (p=0.061), age at first flare-up (p=0.733), severity of disability (p=0.194), history of head trauma (p=0.415) or hearing loss (p=0.237). The radiologic features and the absence of neurological symptoms were consistent with a benign process. Variable signal abnormalities and/or calcifications of the dentate nuclei were noted in all patients, while basal ganglia abnormalities were present in nine subjects. Brain calcifications positively correlated with patients age (p,0.001) and severity of disability (p=0.002). ...
Myositis ossificans progressiva: …the rare progressive type (myositis ossificans progressiva), group after group of muscles become ossified, until the individual is completely rigid. Breathing and swallowing become difficult, and fatal respiratory infections may occur. Steroid treatment of muscle injury and the use of medications to prevent calcification may slow the progression of…
Fibrous dysplasia is the uncommon bone disorder in which, instead of the normal bone, fibrous (scar-like) tissue develops, thus weakening the bone affected and causing it to be fractured or deformed. Only a single bone is usually affected by fibrous dysplasia, and it is most commonly a long bone in the legs or arms or the skull. This is the forum for discussing anything related to this health condition
Principal Investigator:Kitoh Hiroshi, Project Period (FY):2015-04-01 - 2018-03-31, Research Category:Grant-in-Aid for Challenging Exploratory Research, Research Field:Orthopaedic surgery
Heterotopic ossification is a pathological, non neoplastic process of bone formation at ectopic sites, especially inside mesenchymal soft tissues. The disorder can occur localized or generalized.. Local forms are mostly assigned to the entity of Myositis ossificans circumscripta and involve the skeletal muscles. As a result of trauma, often following total hip replacement, or due to neuropathic disorders, e.g. spinal cord lesions, an intramuscular osteogenesis occurs. The osteogenic stimulation of mesenchymal stem cells seems to be the cause, but the pathobiochemical pathways are not known exactly [1].. The generalized disorder Fibrodysplasia ossificans progressiva (FOP, syn. Myositis ossificans progressiva) is a rare connective tissue desease with autosomal dominant heredity. It is characterized by enchondral ossification of muscle, tendons and ligaments after simple injuries, e.g. intramuscular injection [2-4]. The influence of bone morphogenetic proteins on this disorder seems to be evident ...
The term heterotopic ossification (HO) describes bone formation at an abnormal anatomical site, usually in soft tissue. HO can be classified into the following 3 types: Myositis ossificans progressiva (fibrodysplasia ossificans progressiva) - This disorder is among the rarest genetic conditions, with an incidence of 1 case per 2 million persons.
Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high-throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of ...
Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high-throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of ...
Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high-throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of ...
Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high-throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of ...
Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high-throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of ...
Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high-throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of ...
Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high-throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of ...
Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high-throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of ...
Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high-throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of ...
Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high-throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of ...
Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high-throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of ...
Transforming growth factor betas (Tgfbetas) and Bone morphogenetic proteins (Bmps) are pleiotropic cytokines involved in many developmental processes. Organ explant studies have revealed specific roles for Tgfbeta/Bmp ligands in endothelial-mesenchymal transformations (EMT) during the formation of endocardial cushions, precursors of heart valves and septa, and in epicardial-mesenchymal transformations essential for coronary vasculature development. Gene targeting studies in mice demonstrated that the Tgfbetas/Bmps are involved in the ventricular myocardial development and formation of the neural crest-derived aorticopulmonary septum. Tgfbeta/Bmp ligands signal through a repertoire of type I and type II serine/threonine kinase receptors. In our studies, we sought to determine the requirement of Bmp type I receptor Alk2 and Tgfbeta; type I receptor Alk5 for heart development by ablating these receptors specifically in the endocardium (Tie2-Cre), in the myocardium (alphaMHC-Cre and Nkx2.5-Cre), in ...
Heterotopic ossification (HO) is a disabling condition associated with neurologic injury, inflammation, and overactive bone morphogenetic protein (BMP) signaling. The inductive factors involved in lesion formation are unknown. We found that the expression of the neuro-inflammatory factor Substance P (SP) is dramatically increased in early lesional tissue in patients who have either fibrodysplasia ossificans progressiva (FOP) or acquired HO, and in three independent mouse models of HO. In Nse-BMP4, a mouse model of HO, robust HO forms in response to tissue injury; however, null mutations of the preprotachykinin (PPT) gene encoding SP prevent HO. Importantly, ablation of SP+ sensory neurons, treatment with an antagonist of SP receptor NK1r, deletion of NK1r gene, or genetic down-regulation of NK1r-expressing mast cells also profoundly inhibit injury-induced HO. These observations establish a potent neuro-inflammatory induction and amplification circuit for BMP-dependent HO lesion formation, and ...
PHILADELPHIA - An international team of scientists, led by researchers at the University of Pennsylvania School of Medicine, is taking the first step in developing a treatment for a rare genetic disorder called fibrodysplasia ossificans progressiva (FOP), in which the bodys skeletal muscles and soft connective tissue turns to bone, immobilizing patients over a lifetime with a second skeleton.. Reporting in the November issue of the Journal of Clinical Investigation senior authors Eileen Shore, PhD, Professor of Genetics and Orthopedics, and Mary Mullins, PhD, Professor of Cell and Developmental Biology, with scientists in Japan and Germany, demonstrated that the mutation that causes FOP mistakenly activates a cascade of biochemical events in soft tissues that kicks off the process of bone development. The linchpin of the cellular signaling gone awry is a receptor for a bone morphogenetic protein, or BMP.. The present study provides the first clear glimpse of how FOP might develop at a cellular ...
In the present experiments, AP has been measured in Alk1+/− and in Alk1+/+ mice by both tail-cuff and radiotelemetry methods. We have used both methods to measure AP because movement restriction necessary for tail-cuff measurement can modify vasoactive responses, especially when the sympathetic nervous system is involved, and because acute (minutes) effects can be difficult to assess by the tail-cuff method. Besides, both acute and prolonged effects of the vasoactive substances have been recorded because the acute and the long-standing consequences of inhibiting or stimulating these regulatory pathways can be different (Emanueli et al., 1997). Measurements of AP by the tail-cuff method and by telemetry showed consistently higher SAP in Alk1+/− than in Alk1+/+ mice, with no significant differences in HR. It should be noted that arterial hypertension has not been reported as a common sign in individuals with hereditary hemorrhagic telangiectasia type 2, a fact that can be explained by the ...
By January 1999, she was given a diagnosis of fibrodysplasia ossificans progressiva (FOP), a rare genetic disease that causes muscle tissue and connective tissue to turn into bone - gradually forming a second skeleton and making it nearly impossible to move.
Cell culture. iPSCs were maintained in primate embryonic stem (ES) cell medium (ReproCELL) supplemented with 4 ng/ml recombinant human FGF2 (Wako Pure Chemical). To activate the production of induced neural crest cells (iNCCs), mTeSR1 medium (STEMCELL Technologies) was used for the feeder-free culturing of iPSCs. The induction and maintenance of iNCCs and iMSCs derived from iPSCs were previously described (43, 45) (Supplemental Figure 1A). Briefly, iNCCs were induced in chemically defined medium (CDM) supplemented with 10 μM SB-431542 and 1 μM CHIR99021 for 7 days. iNCCs were maintained in CDM supplemented with 10 μM SB-431542, 20 ng/ml FGF2, and 20 ng/ml recombinant human EGF (R&D Systems), and we used up to 20 passages in this study. iMSCs were induced and maintained in αMEM (Invitrogen, Thermo Fisher Scientific) supplemented with 10% (v/v) FBS (Nichirei), 5 ng/ml FGF2, and 0.5% penicillin and streptomycin (Invitrogen, Thermo Fisher Scientific). The FOP-iPSCs used in this study (previously ...
Beginning in early childhood, the muscle, tendons and connective tissue of those afflicted with fibrodysplasia ossificans progressiva simply morph into bone.
Mutations in tumors can create a state of increased cellular plasticity that promotes resistance to treatment. Thus, there is an urgent need to develop novel strategies for identifying key factors that regulate cellular plasticity in order to combat resistance to chemotherapy and radiation treatment. Here we report that prostate epithelial cell reprogramming could be exploited to identify key factors required for promoting prostate cancer tumorigenesis and cellular plasticity. Deletion of phosphatase and tensin homolog (Pten) and transforming growth factor-beta receptor type 2 (Tgfbr2) may increase prostate epithelial cell reprogramming efficiency in vitro and cause rapid tumor development and early mortality in vivo ...
The transforming growth factor‐β (TGF‐β) superfamily constitutes a large family of secreted signaling molecules which are known to have important roles in regulating a wide variety of cellular processes including proliferation, differentiation, adhesion and migration (Roberts and Sporn, 1990; Kingsley, 1994). All known receptors of this superfamily signal through a heteromeric complex of type I and type II transmembrane receptor serine/threonine kinases which act in series (Derynck and Feng, 1997; Massague, 1998). Despite extensive knowledge about the receptor activation mechanisms, which involve recruitment and activation of the type I receptor kinase by the ligand‐activated type II receptor kinase, the downstream signaling pathways from the activated type I receptor are not yet clearly defined. Recently, a set of novel mammalian proteins, termed SMADs, has been identified based on their high homology to the Drosophila Mad and the Caenorhabditis elegans Sma proteins, which were ...